Methods for treating or preventing ophthalmological conditions

ABSTRACT

The present invention relates to methods for treating and preventing ophthalmological disease and disorders, comprising administering Antagonist A or another pharmaceutically acceptable salt thereof, optionally in combination with another treatment, to a subject in need thereof. The present invention also relates to methods for treating and preventing ophthalmological disease and disorders, comprising administering an anti-C5 agent (e.g., ARC1905), optionally in combination with another treatment, to a subject in need thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/434,018, filed Jun. 19, 2019, which is a continuation of U.S.application Ser. No. 14/329,702, filed Jul. 11, 20114, which claims thebenefit of U.S. provisional application nos. 61/845,938, filed Jul. 12,2013, 61/845,935, filed Jul. 12, 2013, 61/845,936, filed Jul. 12, 2013,61/866,502, filed Aug. 15, 2013, 61/866,503, filed Aug. 15, 2013,61/866,507, filed Aug. 15, 2013, 61/911,854, filed Dec. 4, 2013,61/911,860, filed Dec. 4, 2013, 61/911,894, filed Dec. 4, 2013,61/926,812, filed Jan. 13, 2014, 61/926,825, filed Jan. 13, 2014,61/926,848, filed Jan. 13, 2014, 61/931,116, filed Jan. 24, 2014,61/931,125, filed Jan. 24, 2014, and 61/931,135, filed Jan. 24, 2014,each of which is incorporated by reference herein in its entirety.

SEQUENCE LISTING

The Sequence Listing associated with this application is provided intext format in lieu of a paper copy, and is hereby incorporated byreference into the specification. The name of the text file containingthe Sequence Listing is OPHT_012_06US_SeqList_ST25.txt. The text file isabout 372 KB, was created on Jul. 10, 2014, and is being submittedelectronically via EFS-Web.

FIELD OF THE INVENTION

This invention relates to methods and compositions useful for thetreatment or prevention of an ophthalmological disease or disorder,comprising administration of an effective amount of Antagonist A oranother pharmaceutically acceptable salt thereof.

BACKGROUND OF THE INVENTION

Various disorders of the eye are characterized, caused by, or result inchoroidal, retinal or iris neovascularization or retinal edema. One ofthese disorders is macular degeneration. Age-related maculardegeneration (AMD) is a disease that affects approximately one in tenAmericans over the age of 65. One type of AMD, “wet-AMD,” accounts onlyfor approximately 10% of age-related macular degeneration cases butresults in approximately 90% of cases of legal blindness from maculardegeneration in the elderly. Another disorder of the eye is diabeticretinopathy. Diabetic retinopathy can affect up to 80% of all patientshaving diabetes for 10 years or more and is the third leading cause ofadult blindness, accounting for almost 7% of blindness in the USA. Otherdisorders include hypertensive retinopathy, central serouschorioretinopathy, cystoid macular edema, Coats disease and ocular oradnexal neoplasms such as choroidal hemangioma, retinal pigmentepithelial carcinoma, retinal vein occlusions and intraocular lymphoma.

Therefore, although advances in the understanding of the molecularevents accompanying neovascularization have been made, there exists aneed to utilize this understanding to develop improved methods fortreating or preventing neovascular diseases disorders, including ocularneovascular diseases and disorders such as the neovascularization thatoccurs with AMD, diabetic retinopathy, and retinal vein occlusions.

SUMMARY OF THE INVENTION

The present invention relates to methods and compositions useful for thetreatment or prevention of an ophthalmological disease or disorder.

The present invention provides a method for treating or preventing wetage-related macular degeneration (wet AMD), comprising administering toa subject in need thereof (a) Antagonist A or another pharmaceuticallyacceptable salt thereof and (b) an VEGF antagonist, wherein (a) and (b)are administered in an amount that is effective for treating orpreventing wet AMD, and wherein the administering occurs once everymonth, ±about seven days, for a first administration period of at least3 consecutive months, followed by administering (a) and (b) for a secondadministration period at a frequency of at least every other month±about seven days beginning at two months ±about seven days after theday of the last month of the first administration period on which (a)and (b) are administered.

Also provided herein is a method for treating or preventing sub-retinalfibrosis, comprising administering to a subject in need thereof (a)Antagonist A or another pharmaceutically acceptable salt thereof in anamount that is effective for treating or preventing sub-retinalfibrosis.

A method for treating or preventing von Hippel-Lindau (VHL) disease,comprising administering to a subject in need thereof. Antagonist A oranother pharmaceutically acceptable salt thereof in an amount that iseffective for treating or preventing VHL disease is also providedherein.

BRIEF DESCRIPTION OF THE DRAWINGS

Reference is made to the following detailed description, which setsforth illustrative embodiments and the accompanying drawings of which:

FIGS. 1A-F show the chemical structure of Antagonist A, wherein the 5′end of its aptamer (SEQ ID NO: 1) is modified withMe(OCH₂CH₂)_(n)OC(O)NH(CH₂)₄CH(NHC(O)O(CH₂CH₂O)_(n)Me)C(O)NH(CH₂)₆—,where n is about 450. The designations {circle around (B)}-{circlearound (F)} indicate a continuation from a previous panel.

FIG. 2 shows a graph depicting the mean change in visual acuity in wetAMD patients in a phase 2b clinical trial, who were treated with 0.5 mgof Lucentis® alone or with 0.5 mg of Lucentis® and either 1.5 mg ofAntagonist A or 0.3 mg of Antagonist A.

FIG. 3 shows a bar graph showing comparative visual-acuity benefit inwet AMD patients with treatment with 0.5 mg of Lucentis® and either 1.5mg or 0.3 mg of Antagonist A as compared to treatment with Lucentis®monotherapy (0.5 mg).

FIG. 4 shows a graph depicting the early and sustained visual-acuityimprovement over time in wet AMD patients treated with Lucentis®monotherapy (0.5 mg) or with 0.5 mg of Lucentis® and either 1.5 mg ofAntagonist or 0.3 mg of Antagonist A.

FIGS. 5A and 5A provide bar graphs showing that the increased efficacyof treatment with 0.5 mg of Lucentis® and either 1.5 mg or 0.3 mg ofAntagonist A as compared to treatment with Lucentis® monotherapy (0.5mg) in patients with wet AMD is independent of baseline lesion size orbaseline vision. FIG. 5A shows the mean change in visual acuity forpatients in each of the indicated baseline lesion quartiles, and FIG. 5Bshows the mean change in visual acuity for patients with the indicatedbaseline vision.

FIGS. 6A and 6B provide bar graphs showing that the cohort of patientstreated with a combination of 0.5 mg of Lucentis® and 1.5 mg ofAntagonist A included a greater proportion of patients with significantvisual gain (FIG. 6A) and fewer patients with visual loss (FIG. 6B) ascompared to the cohort of patients with treated Lucentis® monotherapy(0.5 mg).

FIGS. 7A-C provide bar graphs showing that patients treated with 0.5 mgof Lucentis® and 1.5 mg of Antagonist A exhibited a greater meanimprovement in final visual acuity as compared to patients treated withLucentis® monotherapy (0.5 mg). FIG. 7A shows the percentage of patientswho demonstrated a visual acuity of 20/40 or better; FIG. 7B shows thepercentage of patients who demonstrated a visual acuity of 20/25 orbetter; and FIG. 7C shows the percentage of patients who demonstrated avisual acuity of 20/200 or worse.

FIGS. 8A and 8B provide bar graphs showing increased reduction inchoroidal neovascularization (CNV) lesion size in small and largebaseline CNV lesions in wet AMD patients treated with both 0.5 mg ofLucentis® and 1.5 mg of Antagonist A as compared to patients treatedwith Lucentis® monotherapy (0.5 mg). FIG. 8A shows the results in allpatients, and FIG. 8B shows the results in patients with a visualoutcome >3-lines.

FIG. 9 shows a graph depicting the mean change in geographic atrophy(GA) lesion area in dry AMD patients measured at 24 weeks in patientstreated with either a 0.3 mg or 1 mg dose of ARC1905 monthly from weeks0 to 24 in a phase 2a trial.

FIG. 10 shows a graph depicting the mean change in GA lesion area in dryAMD patients measured at 24 weeks and 48 weeks in patients treated witheither a 0.3 mg or 1 mg dose of ARC1905 monthly from weeks 0 to 48 in aphase 2a trial.

FIG. 11 shows Early Treatment for Diabetic Retinopathy Study (“ETDRS”)Chart 1.

FIG. 12 shows Early Treatment for Diabetic Retinopathy Study (“ETDRS”)Chart 2.

FIG. 13 shows Early Treatment for Diabetic Retinopathy Study (“ETDRS”)Chart R.

DETAILED DESCRIPTION OF THE INVENTION

In certain aspects, the present invention provides new and improvedmethods and compositions for treating and preventing ophthalmologicaldiseases and disorders, including, e.g., new uses, combinationtherapies, treatment and dosing regimens, and coformulations.

In one aspect, the invention provides methods for treating or preventingan ophthalmological disease or disorder, comprising administering to asubject in need thereof an effective amount of Antagonist A or anotherpharmaceutically acceptable salt thereof. In particular embodiments, thesubject is administered Antagonist A or another pharmaceuticallyacceptable salt thereof and not administered an anti-C5 agent. In someembodiments, the subject is administered Antagonist A or anotherpharmaceutically acceptable salt thereof and not administered a VEGFantagonist.

In particular embodiments, the Antagonist A or another pharmaceuticallyacceptable salt thereof is administered in combination with a VEGFantagonist. In one embodiment, Antagonist A or another pharmaceuticallyacceptable salt thereof is administered in combination with ranibizumab,bevacizumab, aflibercept, pegaptanib sodium, or ESBA1008.

In particular embodiments, the Antagonist A or another pharmaceuticallyacceptable salt thereof is administered in combination with a VEGFantagonist and an anti-C5 agent. In one embodiment, Antagonist A oranother pharmaceutically acceptable salt thereof is administered incombination with a VEGF antagonist (e.g., ranibizumab, bevacizumab,aflibercept, pegaptanib sodium, or ESBA1008), and ARC1905.

The invention also provides treatment regimens, including treatment anddosing regimens, related to the coadministration of Antagonist A oranother pharmaceutically acceptable salt thereof and a VEGF antagonist,optionally also in combination with an anti-C5 agent.

In further embodiments, another agent (e.g., an agent that is notAntagonist A, VEGF antagonist or an anti-C5 agent) that is useful fortreating or preventing an ophthalmological disease or disorder isadministered. In some embodiments, the methods comprise administeringone or more (e.g., two) VEGF antagonists and/or one or more (e.g., two)anti-C5 agents to the subject in need thereof.

In another aspect, the invention provides methods for treating orpreventing an ophthalmological disease or disorder, comprisingadministering to a subject in need thereof an effective amount of ananti-C5 agent (e.g., ARC1905). In particular embodiments, the subject isnot administered Antagonist A or another pharmaceutically acceptablesalt thereof. In some embodiments, the subject is not administered aVEGF antagonist.

In addition, the invention provides coformulations that compriseAntagonist A or another pharmaceutically acceptable salt thereof and aVEGF antagonist. In certain embodiments, the coformulations furthercomprise an anti-C5 agent. In certain embodiments, the coformulationsare pharmaceutically compositions comprising an effective amount ofAntagonist A or another pharmaceutically acceptable salt thereof andVEGF antagonist, and a pharmaceutically acceptable carrier or vehicle.In certain embodiments, the coformulations are pharmaceuticallycompositions comprising an effective amount of Antagonist A or anotherpharmaceutically acceptable salt thereof, VEGF antagonist, and anti-C5agent, and a pharmaceutically acceptable carrier or vehicle.

In one embodiment, the present invention provides methods for treatingor preventing an ophthalmological disease or disorder, comprisingadministering to a subject in need thereof. Antagonist A or anotherpharmaceutically acceptable salt thereof and optionally a VEGFantagonist, wherein the methods further comprise performing a surgery totreat the ophthalmological disease or disorder and/or administration ofan anti-C5 agent.

Definitions and Abbreviations

As used herein, the following terms and phrases shall have the meaningsset forth below. Unless defined otherwise, all technical and scientificterms used herein have the same meaning as commonly understood to one ofskill in the art to which this invention belongs.

The term “about” when used in connection with a referenced numericindication means the referenced numeric indication plus or minus up to10% of that referenced numeric indication. For example, “about 100”means from 90 to 110 and “about six” means from 5.4 to 6.6.

The term “antagonist” refers to an agent that inhibits, either partiallyor fully, the activity or production of a target molecule. Inparticular, the term “antagonist,” as applied selectively herein, meansan agent capable of decreasing levels of gene expression, mRNA levels,protein levels or protein activity of the target molecule. Illustrativeforms of antagonists include, for example, proteins, polypeptides,peptides (such as cyclic peptides), antibodies or antibody fragments,peptide mimetics, nucleic acid molecules, antisense molecules,ribozymes, aptamers, RNAi molecules, and small organic molecules.Illustrative non-limiting mechanisms of antagonist inhibition includerepression of ligand synthesis and/or stability (e.g., using, antisense,ribozymes or RNAi compositions targeting the ligand gene/nucleic acid),blocking of binding of the ligand to its cognate receptor (e.g., usinganti-ligand aptamers, antibodies or a soluble, decoy cognate receptor),repression of receptor synthesis and/or stability (e.g., using,antisense, ribozymes or RNAi compositions targeting the ligand receptorgene/nucleic acid), blocking of the binding of the receptor to itscognate receptor (e.g., using receptor antibodies) and blocking of theactivation of the receptor by its cognate ligand (e.g., using receptortyrosine kinase inhibitors). In addition, the antagonist may directly orindirectly inhibit the target molecule.

The term “antibody fragment” includes a portion of an antibody that isan antigen binding fragment or single chains thereof. An antibodyfragment can be a synthetically or genetically engineered polypeptide.Examples of binding fragments encompassed within the term“antigen-binding portion” of an antibody include (i) a Fab fragment, amonovalent fragment consisting of the V_(L), V_(H), C_(L) and C_(H1)domains; (ii) a F(ab′)₂ fragment, a bivalent fragment comprising two Fabfragments linked by a disulfide bridge at the hinge region; (iii) a Fdfragment consisting of the V_(H) and C_(H1) domains; (iv) a Fv fragmentconsisting of the V_(L) and V_(H) domains of a single arm of anantibody, (v) a dAb fragment (Ward et al., (1989) Nature 341:544-546),which consists of a V_(H) domain; and (vi) an isolated complementaritydetermining region (CDR). Furthermore, although the two domains of theFv fragment, V_(L) and V_(H), are coded for by separate genes, they canbe joined, using recombinant methods, by a synthetic linker that enablesthem to be made as a single protein chain in which the V_(L) and V_(H)regions pair to form monovalent molecules (known as single chain Fv(scFv); see e.g., Bird et al. (1988) Science 242:423-426; and Huston etal. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883). Such single chainantibodies are also intended to be encompassed within the term“antigen-binding fragment” of an antibody. These antibody fragments areobtained using conventional techniques known to those in the art, andthe fragments can be screened for utility in the same manner as wholeantibodies.

The term “aptamer” refers to a peptide or nucleic acid that has aninhibitory effect on a target. Inhibition of the target by the aptamercan occur by binding of the target, by catalytically altering thetarget, by reacting with the target in a way which modifies the targetor the functional activity of the target, by ionically or covalentlyattaching to the target as in a suicide inhibitor or by facilitating thereaction between the target and another molecule. Aptamers can bepeptides, ribonucleotides, deoxyribonucleotides, other nucleic acids ora mixture of the different types of nucleic acids. Aptamers can compriseone or more modified amino acid, bases, sugars, polyethylene glycolspacers or phosphate backbone units as described in further detailherein.

A nucleotide sequence is “complementary” to another nucleotide sequenceif each of the bases of the two sequences matches, i.e., are capable offorming Watson Crick base pairs. The complement of a nucleic acid strandcan be the complement of a coding strand or the complement of anon-coding strand.

The phrase “conserved residue” refers to an amino acid of a group ofamino acids having particular common properties. A functional way todefine common properties among individual amino acids is to analyze thenormalized frequencies of amino acid changes among correspondingproteins of homologous organisms. According to such analyses, groups ofamino acids may be characterized where amino acids within a groupexchange preferentially with each other, and therefore resemble eachother most in their impact on the overall protein structure (Schulz, G.E. and R. H. Schirmer, Principles of Protein Structure,Springer-Verlag). Examples of amino acid groups defined in this mannerinclude:

(i) a charged group, consisting of Glu and Asp, Lys, Arg and His,

(ii) a positively-charged group, consisting of Lys, Arg and His,

(iii) a negatively-charged group, consisting of Glu and Asp,

(iv) an aromatic group, consisting of Phe, Tyr and Trp,

(v) a nitrogen ring group, consisting of His and Trp,

(vi) a large aliphatic nonpolar group, consisting of Val, Leu and Ile,

(vii) a slightly-polar group, consisting of Met and Cys,

(viii) a small-residue group, consisting of Ser, Thr, Asp, Asn, Gly,Ala, Glu, Gln and Pro,

(ix) an aliphatic group consisting of Val, Leu, Ile, Met and Cys, and

(x) a small hydroxyl group consisting of Ser and Thr.

Members of each of the above groups are conserved residues.

The term “label” includes, but is not limited to, a radioactive isotope,a fluorophore, a chemiluminescent moiety, an enzyme, an enzymesubstrate, an enzyme cofactor, an enzyme inhibitor, a dye, a metal ion,a ligand (e.g., biotin or a hapten) and the like. Examples offluorophore labels include fluorescein, rhodamine, dansyl,umbelliferone, Texas red, luminol, NADPH, alpha-beta-galactosidase andhorseradish peroxidase.

The term “nucleic acid” refers to a polynucleotide such asdeoxyribonucleic acid (DNA) or ribonucleic acid (RNA). The term alsoincludes analogs of RNA or DNA made from nucleotide analogs, and, asapplicable to the embodiment being described, single (sense orantisense) and double-stranded polynucleotides, ESTs, chromosomes,cDNAs, mRNAs, and rRNAs.

The terms “RNA interference,” “RNAi,” “miRNA,” and “siRNA” refer to anymethod by which expression of a gene or gene product is decreased byintroducing into a target cell one or more double-stranded RNAs, whichare homologous to a gene of interest (particularly to the messenger RNAof the gene of interest, e.g., PDGF or VEGF).

The term “neovascularization” refers to new blood vessel formation inabnormal tissue or in abnormal positions.

The term “angiogenesis” refers to formation of new blood vessels innormal or in abnormal tissue or positions.

The term “ophthalmological disease” includes diseases of the eye and theocular adnexa.

The term “ocular neovascular disorder” refers to an ocular disordercharacterized by neovascularization. In one embodiment, the ocularneovascular disorder is a disorder other than cancer. Examples of ocularneovascular disorders include diabetic retinopathy and age-relatedmacular degeneration.

The term “mammal” includes a human, monkey, cow, hog, sheep, horse, dog,cat, rabbit, rat and mouse. In certain embodiments, a subject is amammal.

The term “PDGF” refers to a platelet-derived growth factor thatregulates cell growth or division. As used herein, the term “PDGF”includes the various subtypes of PDGF including PDGF-B (see SEQ ID NOS:2 (nucleic acid) and 3 (polypeptide)), PDGF-A (see SEQ ID NOS: 4(nucleic acid) and 5 (polypeptide), PDGF-C (see SEQ ID NOS: 6 (nucleicacid) and 7 (polypeptide)), PDGF-D, variants 1 (see SEQ ID NOS: 8(nucleic acid) and 9 (polypeptide)) and 2 (see SEQ ID NOS: 10 (nucleicacid) and 11 (polypeptide)), and dimerized forms thereof, includingPDGF-AA, PDGF-AB, PDGF-BB, PDGF-CC, and PDGF-DD. Platelet derived growthfactors includes homo- or heterodimers of A-chain (PDGF-A) and B-chain(PDGF-B) that exert their action via binding to and dimerization of tworelated receptor tyrosine kinase platelet-derived growth factor cellsurface receptors (i.e., PDGFRs), PDGFR-α (see SEQ ID NOS: 12 (nucleicacid) and 13 (polypeptide)) and PDGFR-β (see SEQ ID NOS: 14 (nucleicacid) and 15 (polypeptide)). In addition, PDGF-C and PDGF-D, twoadditional protease-activated ligands for the PDGFR complexes, have beenidentified (Li et al., (2000) Nat. Cell. Biol. 2: 302-9; Bergsten etal., (2001) Nat. Cell. Biol. 3: 512-6; and Uutele et al., (2001)Circulation 103: 2242-47). Due to the different ligand bindingspecificities of the PDGFRs, it is known that PDGFR-α/α binds PDGF-AA,PDGF-BB, PDGF-AB, and PDGF-CC; PDGFR-β/β binds PDGF-BB and PDGF-DD;whereas PDGFR-α/β binds PDGF-AB, PDGF-BB, PDGF-CC, and PDGF-DD(Betsholtz et al., (2001) BioEssays 23: 494-507). As used herein, theterm “PDGF” also refers to those members of the class of growth factorsthat induce DNA synthesis and mitogenesis through the binding andactivation of a PDGFR on a responsive cell type. PDGFs can effect, forexample: directed cell migration (chemotaxis) and cell activation;phospholipase activation; increased phosphatidylinositol turnover andprostaglandin metabolism; stimulation of both collagen and collagenasesynthesis by responsive cells; alteration of cellular metabolicactivities, including matrix synthesis, cytokine production, andlipoprotein uptake; induction, indirectly, of a proliferative responsein cells lacking PDGF receptors; and potent vasoconstrictor activity.The term “PDGF” can be used to refer to a “PDGF” polypeptide, a “PDGF”encoding gene or nucleic acid, or a dimerized form thereof.

The term “PDGF-A” refers to an A chain polypeptide of PDGF or itscorresponding encoding gene or nucleic acid.

The term “PDGF-B” refers to a B chain polypeptide of PDGF or itscorresponding encoding gene or nucleic acid.

The term “PDGF-C” refers to a C chain polypeptide of PDGF or itscorresponding encoding gene or nucleic acid.

The term “PDGF-D” refers to a D chain polypeptide of PDGF or itscorresponding encoding gene or nucleic acid, including variants 1 and 2of the D chain polypeptide of PDGF.

The term “PDGF-AA” refers to a dimer having two PDGF-A chainpolypeptides.

The term “PDGF-AB” refers to a dimer having one PDGF-A chain polypeptideand one PDGF-B chain polypeptide.

The term “PDGF-BB” refers to a dimer having two PDGF-B chainpolypeptides.

The term “PDGF-CC” refers to a dimer having two PDGF-C chainpolypeptides.

The term “PDGF-DD” refers to a dimer having two PDGF-D chainpolypeptides.

The term “VEGF” refers to a vascular endothelial growth factor thatinduces angiogenesis or an angiogenic process. As used herein, the term“VEGF” includes the various subtypes of VEGF (also known as vascularpermeability factor (VPF) and VEGF-A) (see SEQ ID NOS: 16 (nucleic acid)and 17 (polypeptide)) that arise by, e.g., alternative splicing of theVEGF-A/VPF gene including VEGF₁₂₁, VEGF₁₆₅ and VEGF₁₈₉. Further, as usedherein, the term “VEGF” includes VEGF-related angiogenic factors such asPIGF (placenta growth factor), VEGF-B, VEGF-C, VEGF-D and VEGF-E, whichact through a cognate VEFG receptor (i.e., VEGFR) to induce angiogenesisor an angiogenic process. The term “VEGF” includes any member of theclass of growth factors that binds to a VEGF receptor such as VEGFR-1(Flt-1) (see SEQ ID NOS: 18 (nucleic acid) and 19 (polypeptide)),VEGFR-2 (KDR/Flk-1) (see SEQ ID NOS: 20 (nucleic acid) and 21(polypeptide)), or VEGFR-3 (FLT-4). The term “VEGF” can be used to referto a “VEGF” polypeptide or a “VEGF” encoding gene or nucleic acid.

The term “PDGF antagonist” refers to an agent that reduces, or inhibits,either partially or fully, the activity or production of a PDGF. Incertain embodiments, the PDGF antagonist inhibits one or more of PDGF-A,PDGF-B, PDGF-C and PDGF-D. In certain embodiments, the PDGF antagonistinhibits one or more of PDGF-A, PDGF-B, and PDGF-C. In some embodiments,the PDGF antagonist inhibits a dimerized form of PDGF, such as PDGF-AA,PDGF-AB, PDGF-BB, PDGF-CC, and PDGF-DD. In certain embodiments, the PDGFantagonist inhibits PDGF-BB. In other embodiments, the PDGF antagonistinhibits PDGF-AB. A PDGF antagonist can directly or indirectly reduce orinhibit the activity or production of a specific PDGF such as PDGF-B.Furthermore, “PDGF antagonists” consistent with the above definition of“antagonist,” include agents that act on a PDGF ligand or its cognatereceptor so as to reduce or inhibit a PDGF-associated receptor signal.Examples of “PDGF antagonists” include antisense molecules, ribozymes orRNAi that target a PDGF nucleic acid; anti-PDGF aptamers, anti-PDGFantibodies to PDGF itself or its receptor, or soluble PDGF receptordecoys that prevent binding of a PDGF to its cognate receptor; antisensemolecules, ribozymes or RNAi that target a cognate PDGF receptor (PDGFR)nucleic acid; anti-PDGFR aptamers or anti-PDGFR antibodies that bind toa cognate PDGFR receptor; and PDGFR tyrosine kinase inhibitors.

The term “VEGF antagonist” refers to an agent that reduces, or inhibits,either partially or fully, the activity or production of a VEGF. Incertain embodiments, the VEGF antagonist inhibits one or more of VEGF-A,VEGF-B, VEGF-C and VEGF-D. A VEGF antagonist can directly or indirectlyreduce or inhibit the activity or production of a specific VEGF such asVEGF₁₆₅. Furthermore, “VEGF antagonists” consistent with the abovedefinition of “antagonist,” include agents that act on either a VEGFligand or its cognate receptor so as to reduce or inhibit aVEGF-associated receptor signal. Examples of “VEGF antagonists” includeantisense molecules, ribozymes or RNAi that target a VEGF nucleic acid;anti-VEGF aptamers, anti-VEGF antibodies to VEGF itself or its receptor,or soluble VEGF receptor decoys that prevent binding of a VEGF to itscognate receptor; antisense molecules, ribozymes, or RNAi that target acognate VEGF receptor (VEGFR) nucleic acid; anti-VEGFR aptamers oranti-VEGFR antibodies that bind to a cognate VEGFR receptor; and VEGFRtyrosine kinase inhibitors. In certain embodiments, the VEGF antagonistis a peptide, e.g., a peptide comprising three or more amino acidresidues. In certain embodiments, the VEGF antagonist is a bicyclicpeptide.

The term “effective amount” when used in connection with an activeagent, refers to an amount of the active agent, e.g., a PDGF antagonist,a VEGF antagonist or an anti-C5 agent, alone or in combination withanother active agent, that is useful to treat or prevent anophthalmological disease or disorder. The “effective amount” can varydepending upon the mode of administration, specific locus of theophthalmological disease or disorder, the age, body weight, and generalhealth of the subject. The effective amount of two or more active agentsis the combined amount of the active agents that is useful for treatingor preventing an ophthalmological disease or disorder, even if theamount of one of the agents, in the absence of one or more of the otheragents, is ineffective to treat or prevent the ophthalmological diseaseor disorder.

A “variant” of polypeptide X refers to a polypeptide having the aminoacid sequence of polypeptide X in which is altered in one or more aminoacid residues. The variant can have “conservative” changes, wherein asubstituted amino acid has similar structural or chemical properties(e.g., replacement of leucine with isoleucine). More rarely, a variantcan have “nonconservative” changes (e.g., replacement of glycine withtryptophan). Analogous minor variations may also include amino aciddeletions or insertions, or both. Guidance in determining which aminoacid residues may be substituted, inserted, or deleted withouteliminating biological or immunological activity can be determined usingcomputer programs well known in the art, for example, LASERGENE software(DNASTAR).

The term “variant,” when used in the context of a polynucleotidesequence, can encompass a polynucleotide sequence related to that ofgene or the coding sequence thereof. This definition also includes, forexample, “allelic,” “splice,” “species,” or “polymorphic” variants. Asplice variant can have significant identity to a reference molecule,but will generally have a greater or lesser number of polynucleotidesdue to alternative splicing of exons during mRNA processing. Thecorresponding polypeptide can possess additional functional domains oran absence of domains. Species variants are polynucleotide sequencesthat vary from one species to another. The resulting polypeptidesgenerally will have significant amino acid identity relative to eachother. A polymorphic variant is a variation in the polynucleotidesequence of a particular gene between individuals of a given species.

The term “anti-C5 agent” refers to an agent that reduces, or inhibits,either partially or fully, the activity or production of a C5 complementprotein or a variant thereof. An anti-C5 agent can directly orindirectly reduce or inhibit the activity or production of a C5complement protein or variant thereof. An anti-C5 agent can reduce orinhibit the conversion of C5 complement protein into its componentpolypeptides C5a and C5b. Anti-C5 agents can also reduce or inhibit theactivity or production of C5a and/or C5b. Examples of “anti-C5 agents”include antisense molecules, ribozymes or RNAi that target a C5 nucleicacid; anti-C5 aptamers including anti-C5a and anti-C5b aptamers, anti-C5antibodies directed against C5, C5a, C5b, or C5b-9, or soluble C5receptor decoys that prevent binding of a C5 complement protein orvariant or fragment thereof (e.g., C5a or C5b) to a binding partner orreceptor.

Agents Useful for Treatment or Prevention of an Opthalmological Diseaseor Disorder

Antagonist A

Antagonist A is a PEGylated, anti-PDGF aptamer having the sequenceCAGGCUACGC GTAGAGCAUC ATGATCCUGT (SEQ ID NO: 1) (see Example 3 of USPatent Application Publication No. 20050096257, incorporated herein byreference in its entirety) having 2′-fluoro-2′-deoxyuridine at positions6, 19 and 28; 2′-fluoro-2′-deoxycytidine at positions 8, 20, 26, and 27;2′-O-Methyl-2′-deoxyguanosine at positions 9, 14, 16, and 29;2′-O-Methyl-2′-deoxyadenosine at position 21; an inverted orientation T(i.e., 3′-3′-linked) at position 30; and two heaxethylene-glycolphosphoramidite linkages that join together the 9^(th) and 10^(th)nucleotides and 21^(st) and 22^(nd) nucleotides via phosphodiesterlinkages between the linker and the respective nucleotides.

The chemical name of Antagonist A is [(monomethoxy 20K polyethyleneglycol carbamoyl-N2-) (monomethoxy 20K polyethylene glycolcarbamoyl-N6-)]-lysine-amido-6-hexandilyl-(1-5′)-2′-deoxycytidylyl-(3′-5′)-2′-deoxyadenylyl-(3′-5′)-2′-deoxyguanylyl-(3′-5′)-2′-deoxyguanylyl-(3′-5)-2′-deoxycytidylyl-(3′-5)-2′-deoxy-2′-fluorouridylyl-(3′-5′)-2′-deoxyadenylyl-(3′-5)-2′-deoxy-2′-fluorocytidylyl-(3′-5)-2′-deoxy-2′-methoxyguanylyl-(3′-1)-PO₃-hexa(ethyloxy)-(18-5)-2′-deoxycytidylyl-(3′-5′)-2′-deoxyguanylyl-(3′-5′)-thymidylyl-(3′-5)-2′-deoxyadenylyl-(3′-5′)-2′-deoxy-2′-methoxyguanylyl-(3′-5)-2′-deoxyadenylyl-(3′-5)-2′-deoxy-2′-methoxyguanylyl-(3′-5)-2′-deoxycytidylyl-(3′-5)-2′-deoxyadenylyl-(3′-5)-2′-deoxy-2′-fluorouridylyl-(3′-5)-2′-deoxy-2′-fluorocytidylyl-(3′-5)-2′-deoxy-2′-methoxyadenylyl-(3′-1)-PO₃-hexa(ethyloxy)-(18-5)-thymidylyl-(3′-5)-2′-deoxyguanylyl-(3′-5)-2′-deoxyadenylyl-(3′-5)-thymidylyl-(3′-5)-2′-deoxy-2′-fluorocytidylyl-(3′-5)-2′-deoxy-2′-fluorocytidylyl-(3′-5)-2′-deoxy-2′-fluorouridylyl-(3′-5)-2′-deoxy-2′-methoxyguanylyl-(3′-3)-thymidine.

The structure of Antagonist A is shown in FIG. 1.

The sequence of Antagonist A is:

5′-[mPEG2 40 kD]-[HN—(CH₂)₆O] CAGGCU_(f)AC_(f)G_(m) [PO₃(CH₂CH₂O)₆]CGTAG_(m)AG_(m)CAU_(f)C_(f)A_(m)[PO₃(CH₂CH₂O)₆]TGATC_(f)C_(f)U_(f)G_(m)-[3T]-3′, whose aptamer sequenceis set forth in (SEQ ID NO: 1),

where [3T] refers to an inverted thymidine nucleotide that is attachedto the 3′ end of the oligonucleotide at the 3′ position on the ribosesugar, and [mPEG2 40 kD] represents two 20 kD polyethylene glycol (PEG)polymer chains, in one embodiment two about 20 kD PEG polymer chains,that are covalently attached to the two amino groups of a lysine residuevia carbamate linkages. This moiety is in turn linked with theoligonucleotide via the amino linker described below.

[HN—(CH₂)₆O] represents a bifunctional α-hydroxy-w-amino linker that iscovalently attached to the PEG polymer via an amide bond. The linker isattached to the oligonucleotide at the 5′-end of Antagonist A by aphosphodiester linkage.

[PO₃(CH₂CH₂O)₆] represents the hexaethylene glycol (HEX) moieties thatjoin segments of the oligonucleotide via phosphodiester linkages.Antagonist A has two HEX linkages that join together the 9^(th) and10^(th) nucleotides and 21^(st) and 22^(nd) nucleotides viaphosphodiester linkages between the linker and the respectivenucleotides.

C, A, G, and T represent the single letter code for the 2′-deoxyderivatives of cytosine, adenosine, guanosine, and thymidine nucleicacids, respectively. Antagonist A has four 2′-deoxyribocytosine, six2′-deoxyriboadenosine, four 2′-deoxyriboguanosine, and four2′-deoxyribothymidine.

G_(m) and A_(m) represent 2′-methoxy substituted forms of guanosine andadenosine, respectively. Antagonist A has four 2′-methoxyguanosines andone 2′-methoxyadenosine. C_(f) and U_(f) represent the 2′-fluorosubstituted forms of cytosine and uridine, respectively. Antagonist Ahas four 2′-fluorocytosines and three 2′-fluorouridines.

The phosphodiester linkages in the oligonucleotide, with the exceptionof the 3′-terminus, connect the 5′- and 3′-oxygens of the ribose ringwith standard nucleoside phosphodiester linkages. The phosphodiesterlinkage between the 3′-terminal thymidine and the penultimate G_(m)links their respective 3′-oxygens, which is referred to as the3′,3′-cap.

Antagonist A has a molecular weight from 40,000 to 60,000 Daltons, inone embodiment from about 40,000 to about 60,000 Daltons, and can becolorless to slightly yellow in solution. Antagonist A can be present ina solution of monobasic sodium phosphate monohydrate and dibasic sodiumphosphate heptahydrate as buffering agents and sodium chloride as atonicity adjuster. Antagonist A is a hydrophilic polymer. The AntagonistA is soluble in water and in phosphate-buffered saline (PBS), asassessed by visual inspection, to at least 50 mg (based onoligonucleotide weight)/mL solution.

Antagonist A can be synthesized using an iterative chemical synthesisprocedure to produce the oligonucleotide portion, which is thencovalently bonded to a pegylation reagent, as further described inExample 4 of US Patent Publication NO. 2012/0100136.

Antagonist A is a persodium salt. Other pharmaceutically acceptablesalts, however, of Antagonist are useful in the compositions and methodsdisclosed herein.

VEGF Antagonists

In some embodiments, the VEGF antagonist is ranibizumab (commerciallyavailable under the trademark Lucentis® (Genentech, San Francisco,Calif.); see FIG. 1 of U.S. Pat. No. 7,060,269 for the heavy chain andlight chain variable region sequences), bevacizumab (commerciallyavailable under the trademark Avastin® (Genentech, San Francisco,Calif.); see FIG. 1 of U.S. Pat. No. 6,054,297 for the heavy chain andlight chain variable region sequences), aflibercept (commerciallyavailable under the trademark Eylea® (Regeneron, Tarrytown, N.Y.), KH902VEGF receptor-Fc fusion protein (see Zhang et al. (2008) Mol Vis.14:37-49), 2C3 antibody (see U.S. Pat. No. 6,342,221, Column 8, lines48-67, Column 9, lines 1-21), ORA102 (available from Ora Bio, Ltd.),pegaptanib (e.g., pegaptanib sodium; commercially available under thetrademark Macugen® (Valeant Pharmaceuticals, Bridgewater, N.J.; see FIG.1 of U.S. Pat. No. 6,051,698)), bevasiranib (see Dejneka et al. (2008)Mol Vis. 14:997-1005), SIRNA-027 (Shen et al. (2006) Gene Ther.13:225-34), decursin (see U.S. Pat. No. 6,525,089 (Column 3, lines5-16)), decursinol (see Ahn et al. (1997) Planta Med. 63:360-1),picropodophyllin (see Economou (2008) Investigative Ophthalmology &Visual Science. 49:2620-6), guggulsterone (see Kim et al. (2008) Oncol.Rep. 20:1321-7), PLG101 (see Ahmadi and Lim (2008) Expert OpinPharmacother. 9:3045-52), PLG201 (see Ahmadi and Lim (2008)), eicosanoidLXA4 (see Baker et al (2009) J Immun. 182:3819-26), PTK787 (commerciallyavailable under the trademark Vitalanib™; see Barakat and Kaiser (2009)Expert Opin Investig Drugs 18:637-46), pazopanib (see Takahashi et al.(2009) Arch Ophthalmol. 127:494-9), axitinib (see Hu-Lowe et al. (2008)Clin Cancer Res. 14:7272-83), CDDO-Me (see Sogno et al. (2009) RecentResults Cancer Res. 181:209-12), CDDO-Imm (see Sogno et al. (2009)),shikonin (see Hisa et al. (1998) Anticancer Res. 18:783-90),beta-hydroxyisovalerylshikonin (see Hisa et al. (1998)), ganglioside GM3(Chung et al. (2009) Glycobio. 19:229-39), DC101 antibody (see U.S. Pat.No. 6,448,077, Column 2, lines 61-65), Mab25 antibody (see U.S. Pat. No.6,448,077, Column 2, lines 61-65), Mab73 antibody (see U.S. Pat. No.6,448,077, Column 2, lines 61-65), 4A5 antibody (see U.S. Pat. No.6,383,484, Column 12, lines 50-54), 4E10 antibody (see U.S. Pat. No.6,383,484, Column 10, lines 66-67, Column 11, lines 1-2), 5F12 antibody(see U.S. Pat. No. 6,383,484, Column 10, lines 62-65), VA01 antibody(see U.S. Pat. No. 5,730,977, Column 6, lines 26-30), BL2 antibody (U.S.Pat. No. 5,730,977, Column 6, lines 30-32), VEGF-related protein (seeU.S. Pat. No. 6,451,764, FIG. 1), sFLT01 (see Pechan et al. (2009) GeneTher. 16:10-6), sFLT02 (see Pechan et al. (2009)), Peptide B3 (see Lacalet al. (2008) Eur J Cancer 44:1914-21), TG100801 (see Palanki et al.(2008) J Med Chem. 51:1546-59), sorafenib (commercially available underthe trademark Nexavar™; see Kernt et al. (2008) Acta Ophthalmol.86:456-8), G6-31 antibody (see Crawford et al. (2009) Cancer Cell15:21-34), ESBA1008 (see U.S. Pat. No. 8,349,322), tivozanib (see U.S.Pat. No. 6,821,987, incorporated by reference in its entirety; Campas etal. (2009) Drugs Fut 2009, 34(10): 793), or a pharmaceuticallyacceptable salt thereof.

In another embodiment, the VEGF antagonist is an antibody or an antibodyfragment which binds to an epitope VEGF-A (SEQ ID NO: 22) or VEGF-B (SEQID NO: 23), or any portion of the epitopes. In one embodiment, the VEGFantagonist is an antibody or antibody fragment that binds to one or moreof an epitope of VEGF (e.g., SEQ ID NOS: 22 and 23). In anotherembodiment, the VEGF antagonist is an antibody or an antibody fragmentwhich binds to an epitope of VEGF, such as an epitope of VEGF-A, VEGF-B,VEGF-C, VEGF-D, or VEGF-E. In some embodiments, the VEGF antagonistbinds to an epitope of VEGF such that binding of VEGF and VEGFR areinhibited. In one embodiment, the epitope encompasses a component of thethree dimensional structure of VEGF that is displayed, such that theepitope is exposed on the surface of the folded VEGF molecule. In oneembodiment, the epitope is a linear amino acid sequence from VEGF.

In some embodiments, an inhibitory antibody directed against VEGF isknown in the art, e.g., those described in U.S. Pat. Nos. 6,524,583,6,451,764 (VRP antibodies), 6,448,077, 6,416,758, 6,403,088 (to VEGF-C),6,383,484 (to VEGF-D), 6,342,221 (anti-VEGF antibodies), 6,342,2196,331,301 (VEGF-B antibodies), and 5,730,977, and PCT publicationsWO96/30046, WO 97/44453, and WO 98/45331, the contents of which areincorporated by reference in their entirety.

Other non-antibody VEGF antagonists include antibody mimetics (e.g.,Affibody® molecules, affilins, affitins, anticalins, avimers, Kunitzdomain peptides, and monobodies) with VEGF antagonist activity. Thisincludes recombinant binding proteins comprising an ankyrin repeatdomain that binds VEGF-A and prevents it from binding to VEGFR-2. Oneexample is MP0112, also known as AGN 150998 (DARPin®). The ankyrinbinding domain may have an amino acid sequence of SEQ ID NO: 97.

Recombinant binding proteins comprising an ankyrin repeat domain thatbinds VEGF-A and prevents it from binding to VEGFR-2 are described inmore detail in WO2010/060748 and WO2011/135067.

Further specific antibody mimetics with VEGF antagonist activity are the40 kD pegylated anticalin PRS-050 and the monobody angiocept (CT-322).

The aforementioned non-antibody VEGF antagonist may be modified tofurther improve their pharmacokinetic properties or bioavailability. Forexample, a non-antibody VEGF antagonist may be chemically modified(e.g., pegylated) to extend its in vivo half-life. Alternatively or inaddition, it may be modified by glycosylation or the addition of furtherglycosylation sites not present in the protein sequence of the naturalprotein from which the VEGF antagonist was derived.

Other non-antibody VEGF antagonist immunoadhesin currently inpre-clinical development is a recombinant human soluble VEGF receptorfusion protein similar to VEGF-trap containing extracellularligand-binding domains 3 and 4 from VEGFR2/KDR, and domain 2 fromVEGFR1/Flt-1; these domains are fused to a human IgG Fc protein fragment(Li et al., 2011 Molecular Vision 17:797-803). This antagonist binds toisoforms VEGF-A. VEGF-B and VEGF-C. The molecule is prepared using twodifferent production processes resulting in different glycosylationpatterns on the final proteins. The two glycoforms are referred to asKH902 (conbercept) and KH906. The fusion protein can have the amino acidsequence of SEQ ID NO: 98 and, like VEGF-trap, can be present as adimer. This fusion protein and related molecules are furthercharacterized in EP1767546.

Anti-C5 Agents

In certain embodiments, the anti-C5 agent modulates a function of a C5complement protein or a variant thereof. In some embodiments, theanti-C5 agent inhibits a function of C5 complement protein or a variantthereof. In one embodiment, the function inhibited by the anti-C5 agentis C5 complement protein cleavage.

A C5 complement protein variant as used herein encompasses a variantthat performs substantially the same function as a C5 complement proteinfunction. A C5 complement protein variant in some embodiments comprisessubstantially the same structure and in some embodiments comprises atleast 80% sequence identity, in some embodiments at least 90% sequenceidentity, and in some embodiments at least 95% sequence identity to theamino acid sequence of the C5 complement protein comprising the aminoacid sequence SEQ ID NO: 24.

In some embodiments, the anti-C5 agent is selected from a nucleic acidmolecule, an aptamer, an antisense molecule, an RNAi molecule, aprotein, a peptide, a cyclic peptide, an antibody or antibody fragment,a sugar, a polymer, or a small molecule. In certain embodiments, theanti-C5 agent is an anti-C5 agent described in PCT Patent ApplicationPublication No. WO 2007/103549.

In particular embodiments, the anti-C5 agent is an anti-C5 aptamer.Aptamers are nucleic acid molecules having specific binding affinity tomolecules through interactions other than classic Watson-Crick basepairing. Aptamers, like peptides generated by phage display ormonoclonal antibodies (“mAbs”), are capable of specifically binding toselected targets and modulating the target's activity, e.g., throughbinding aptamers may block their target's ability to function. Theaptamers may be unpegylated or pegylated. In particular embodiments, theaptamers may contain one or more 2′ sugar modifications, such as2′-O-alkyl (e.g., 2′-O-methyl or 2′-O-methoxyethyl) or 2′-fluoromodifications.

Illustrative C5 specific aptamers include the aptamers disclosed in PCTPublication No. WO 2007/103549, which is incorporated by reference inits entirety. Illustrative C5 specific aptamers include the aptamersARC185 (SEQ ID NO: 25), ARC186 (SEQ ID NO: 26), ARC188 (SEQ ID NO: 27),ARC189 (SEQ ID NO: 28), ARC243 (SEQ ID NO: 29), ARC244 (SEQ ID NO: 30),ARC250 (SEQ ID NO: 31), ARC296 (SEQ ID NO: 32), ARC297 (SEQ ID NO: 33),ARC330 (SEQ ID NO: 34), ARC331 (SEQ ID NO: 35), ARC332 (SEQ ID NO: 36),ARC333 (SEQ ID NO: 37), ARC334 (SEQ ID NO: 38), ARC411 (SEQ ID NO: 39),ARC412 (SEQ ID NO: 40), ARC413 (SEQ ID NO: 41), ARC414 (SEQ ID NO: 42),ARC415 (SEQ ID NO: 43), ARC416 (SEQ ID NO: 44), ARC417 (SEQ ID NO: 45),ARC418 (SEQ ID NO: 46), ARC419 (SEQ ID NO: 47), ARC420 (SEQ ID NO: 48),ARC421 (SEQ ID NO: 49), ARC422 (SEQ ID NO: 50), ARC423 (SEQ ID NO: 51),ARC424 (SEQ ID NO: 52), ARC425 (SEQ ID NO: 53), ARC426 (SEQ ID NO: 54),ARC427 (SEQ ID NO: 55), ARC428 (SEQ ID NO: 56), ARC429 (SEQ ID NO: 57),ARC430 (SEQ ID NO: 58), ARC431 (SEQ ID NO: 59), ARC432 (SEQ ID NO: 60),ARC433 (SEQ ID NO: 61), ARC434 (SEQ ID NO: 62), ARC435 (SEQ ID NO: 63),ARC436 (SEQ ID NO: 64), ARC437 (SEQ ID NO: 65), ARC438 (SEQ ID NO: 66),ARC439 (SEQ ID NO: 67), ARC440 (SEQ ID NO: 68), ARC457 (SEQ ID NO: 69),ARC458 (SEQ ID NO: 70), ARC459 (SEQ ID NO: 71), ARC473 (SEQ ID NO: 72),ARC522 (SEQ ID NO: 73), ARC523 (SEQ ID NO: 74), ARC524 (SEQ ID NO: 75),ARC525 (SEQ ID NO: 76), ARC532 (SEQ ID NO: 77), ARC543 (SEQ ID NO: 78),ARC544 (SEQ ID NO: 79), ARC550 (SEQ ID NO: 80), ARC551 (SEQ ID NO: 81),ARC552 (SEQ ID NO: 82), ARC553 (SEQ ID NO: 83), ARC554 (SEQ ID NO: 84),ARC657 (SEQ ID NO: 85), ARC658 (SEQ ID NO: 86), ARC672 (SEQ ID NO: 87),ARC706 (SEQ ID NO: 88), ARC913 (SEQ ID NO: 89), ARC874 (SEQ ID NO: 90),ARC954 (SEQ ID NO: 91), ARC1537 (SEQ ID NO: 92), ARC1730 (SEQ ID NO:93), or a pharmaceutically acceptable salt thereof.

In some embodiments, the anti-C5 agent is an aptamer with SEQ ID NO: 94,95, or 96.

In a particular embodiment, the anti-C5 agent is a C5 specific aptamercomprising the nucleotide sequence of SEQ ID NO: 26 conjugated to apolyethylene glycol moiety via a linker. In some embodiments, thepolyethylene glycol moiety has a molecular weight greater than about 10kDa, particularly a molecular weight of about 20 kDa, more particularlyabout 30 kDa and more particularly about 40 kDa. In some embodiments,the polyethylene glycol moiety is conjugated via a linker to the 5′ endof the aptamer. In some embodiments, the PEG conjugated to the 5′ end ofis a PEG of about 40 kDa molecular weight. In particular embodiments theabout 40 kDa PEG is a branched PEG. In some embodiments the branchedabout 40 kDa PEG is 1,3-bis(mPEG-[about 20 kDa])-propyl-2-(4′-butamide).In other embodiments the branched about 40 kDa PEG is2,3-bis(mPEG-[about 20 kDa])-propyl-1-carbamoyl.

In a particular embodiment, the C5 specific aptamer is a compound,ARC187, having the structure set forth below:

or a pharmaceutically acceptable salt thereof, whereAptamer=fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUfUAfCf CfUmGfCmG-3T (SEQ ID NO: 26)

wherein fC and fU=2′-fluoro nucleotides, and mG and mA=2′-OMenucleotides and all other nucleotides are 2′-OH and where 3T indicatesan inverted deoxy thymidine. In some embodiments, each 20 kDa mPEG ofthe above structure has a molecular weight of about 20 kDa.

In another particular embodiment, the C5 specific aptamer is a compound,ARC1905, having the structure set forth below:

or a pharmaceutically acceptable salt thereof, whereAptamer=fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUfUAfCfCfUmGfCmG-3T (SEQ ID NO: 26)

wherein fC and fU=2′-fluoro nucleotides, and mG and mA=2′-OMenucleotides and all other nucleotides are 2′-OH and where 3T indicatesand inverted deoxy thymidine. In some embodiments, each 20 kDa mPEG ofthe above structure has a molecular weight of about 20 kDa.

In other embodiments, the anti-C5 agent is an antisense oligonucleotideor ribozyme targeted to C5 that effects C5 inhibition by inhibitingprotein translation from the messenger RNA or by targeting degradationof the corresponding C5 mRNA.

In still other embodiments, the anti-C5 agent is an anti-C5 RNAinterference (RNAi) construct. Certain double stranded oligonucleotidesuseful to effect RNAi against C5 complement protein are less than 30base pairs in length and may comprise about 25, 24, 23, 22, 21, 20, 19,18 or 17 base pairs of ribonucleic acid and comprise a sequence withsubstantial sequence identity to the mRNA sequence of complement C5protein, particularly human complement C5 protein. Optionally, the dsRNAoligonucleotides may include 3′ overhang ends. Non-limiting illustrative2-nucleotide 3′ overhangs are composed of ribonucleotide residues of anytype and may even be composed of 2′-deoxythymidine resides, which lowersthe cost of RNA synthesis and may enhance nuclease resistance of siRNAsin the cell culture medium and within transfected cells (see Elbashi etal., (2001) Nature, 411: 494-8).

Other Agents for Treatment or Prevention of an Ophthalmological Diseaseor Disorder

In another embodiment, another agent useful for treating or preventingan ophthalmological disease or disorder is volociximab or apharmaceutically acceptable salt thereof (Ramakrishnan et al. (2008) JExp Ther Oncol. 5:273-86, which is hereby incorporated by reference inits entirety).

In some embodiments, a plurality of aptamers can be associated with asingle Non-Immunogenic, High Molecular Weight Compound, such asPolyalkylene Glycol or PEG, or a Lipophilic Compound, such as aglycerolipid. The aptamers can all be to one target or to differenttargets. In embodiments where a compound comprises more than one PDGFaptamer, there can be an increase in avidity due to multiple bindinginteractions with a target, such as PDGF or VEGF. In yet furtherembodiments, a plurality of Polyalkylene Glycol, PEG, glycerol lipidmolecules can be attached to each other. In these embodiments, one ormore aptamers can be associated with each Polyalkylene Glycol, PEG, orglycerol lipid. This can result in an increase in avidity of eachaptamer to its target. In addition, in embodiments where there areaptamers to PDGF or aptamers to PDGF and different Targets associatedwith Polyalkylene Glycol, PEG, or glycerol lipid, a drug can also beassociated with, e.g., covalently bonded to, Polyalkylene Glycol, PEG,or glycerol lipid. Thus the compound would provide targeted delivery ofthe drug, with Polyalkylene Glycol, PEG, or glycerol lipid serving as aLinker, optionally, with one or more additional linkers.

Aptamers can be 5′-capped and/or 3′-capped with a 5′-5′ invertednucleoside cap structure at the 5′ end and/or a 3′-3′ invertednucleoside cap structure at the 3′ end. In several embodiments,Antagonist A, Antagonist B, Antagonist C, Antagonist D, pegaptanib,bevasiranib and Sirna-027 are 5′ or 3′ end-capped.

Methods for Treating or Preventing an Ophthalmological Disease orDisorder

The invention provides methods and compositions useful for treating orpreventing ophthalmological diseases and disorders, including but notlimited to any of the ophthalmological diseases and disorders describedherein.

In some embodiments, the methods for treating or preventing anophthalmological disease or disorder disclosed herein improve retinalattachment success, improve visual acuity, or stabilize vision. In someembodiments, the methods disclosed herein prevent or retard the rate offurther vision loss in a subject.

In some embodiments, administration of Antagonist A or anotherpharmaceutically acceptable salt thereof in combination with a VEGFantagonist or pharmaceutically acceptable salt thereof and/or an anti-C5agent improves retinal attachment success, improves visual acuity, orstabilizes vision to a degree that is greater than administration ofAntagonist A or another pharmaceutically acceptable salt thereof alone,the VEGF antagonist or pharmaceutically acceptable salt thereof alone,or the anti-C5 agent alone. In some embodiments, the administration ofAntagonist A or another pharmaceutically acceptable salt thereof and theVEGF antagonist or pharmaceutically acceptable salt thereof, andoptionally, an anti-C5 agent, has a synergistic effect in treating orpreventing an ophthalmological disease or disorder. For example, theadministration of both Antagonist A or another pharmaceuticallyacceptable salt thereof and a VEGF antagonist or pharmaceuticallyacceptable salt thereof can improve retinal attachment success, improvevisual acuity, or stabilize vision to a degree that is greater than anadditive effect of administering both Antagonist A or anotherpharmaceutically acceptable salt thereof and the VEGF antagonist orpharmaceutically acceptable salt thereof. In some embodiments,administration of Antagonist A, alone or in combination with a VEGFantagonist and/or an anti-C5 agent, according to the methods describedherein, e.g., treatment or dosing regimens, improves retinal attachmentsuccess, improves visual acuity, or stabilizes vision to a degree thatis greater than administration of Antagonist A, alone or in combinationwith a VEGF antagonist and/or an anti-C5 agent, according to previouslydescribed methods.

In particular embodiments, any of the methods and compositions of thepresent invention are used to treat or prevent an ophthalmologicaldisease or disorder in particular subjects. For example, in certainembodiments, subjects treated according to a method described herein aredefined or identified based on their previous treatments for the diseaseor disorder, specific manifestations of their disease or disorder beingtreated, and/or other characteristics. In one embodiment, the subjecthas a defined phenotype or medical history.

Accordingly, any of the methods described herein may further compriseidentifying the subject to be treated, such as by determining whetherthe subject was previously administered a VEGF antagonist for treatingor preventing the disease or disorder or whether the subject hadpreviously failed monotherapy with a VEGF antagonist, e.g., by inquiringof the subject or his health care provider, or by reviewing thesubject's medical records.

In one embodiment, the subject was previously treated with a VEGFantagonist or anti-VEGF monotherapy for any ocular disease or disorderfor which a VEGF antagonist is used, or for any of the ocular diseasesor disorders described herein (e.g., wet-type AMD).

In particular embodiments, the methods and compositions described hereinare useful for treating or preventing an ophthalmological disease ordisorder in a subject who is anti-VEGF resistant, was previouslyadministered or treated with anti-VEGF monotherapy, does not respond orhad not responded favorably or adequately to anti-VEGF monotherapy,and/or failed monotherapy with a VEGF antagonist. In some embodiments, asubject who failed monotherapy is anti-VEGF resistant, hascomplement-mediated inflammation, and/or did not respond adequately toanti-VEGF monotherapy. In one embodiment, the subject who failedmonotherapy with a VEGF antagonist is a subject who experienced a poorvisual or anatomic outcome after treatment or administration with a VEGFantagonist. In one embodiment, the subject did not exhibit improvedvision or exhibited reduced vision following anti-VEGF monotherapy.

In certain embodiments, the subject does not respond or had notresponded favorably or adequately to anti-VEGF monotherapy, asdetermined by the subject's vision loss or by the subject's lack ofsignificant vision gain following anti-VEGF monotherapy. In oneembodiment, the subject's lack of significant vision gain followinganti-VEGF monotherapy is determined by the subject's loss of ability toread one or more, in some embodiments three or more, and in someembodiments fifteen or more, letters of a standardized chart of visiontesting, e.g., the Early Treatment for Diabetic Retinopathy Study Chart(“ETDRS chart”). In some embodiments, the vision testing is as describedin Early Treatment Diabetic Retinopathy Study Research Group (ETDRS),Manual of Operations, Baltimore: ETDRS Coordinating Center, Universityof Maryland. Available from: National Technical Information Service,5285 Port Royal Road, Springfield, Va. 22161; Accession No. PB85223006/AS; Ferris et al., Am J Ophthalmol 94:91-96, 1982; or Example 4,as described herein. In some embodiments, the vision testing uses one ormore charts available fromhttp://www.nei.nih.gov/photo/keyword.asp?conditions=Eye+Charts&match=all,e.g., ETDRS visual acuity Chart 1, 2 and/or R.

In another embodiment, the subject's vision loss following anti-VEGFmonotherapy is determined by the subject's loss of ability to read oneor more, in some embodiments three or more, letters or lines of astandardized chart of vision testing, e.g., the ETDRS chart, frombaseline. In one embodiment, the subject's lack of significant visiongain following anti-VEGF monotherapy is determined by the subject'sinability to read an additional one or more, in some embodiment three ormore, and in some embodiments fifteen or more, letters of a standardizedchart of vision testing, e.g., the ETDRS chart, from baseline. Inanother embodiment, the subject's lack of significant vision gainfollowing anti-VEGF monotherapy is determined by the subject's inabilityto read an additional one or more, in some embodiments three or more,lines of a standardized chart of visual testing, e.g., the ETDRS chart,from baseline. In some embodiments, a subject's vision loss or lack ofsignificant vision gain is determined by the subject's visual loss oranatomic signs of poor treatment response, for example, persistentleakage, increased hemorrhage, persistent or increased retinal pigmentepithelium (RPE) detachment, signs of neovascular activity, or growth ofneovascularization or increased deposition of abnormal matrix orfibrosis. In particular embodiments, a subject's vision loss or lack ofsignificant vision gain is determined at 12 weeks or at 24 weeksfollowing the initiation of treatment.

In certain embodiments, the subject is anti-VEGF-resistant to a VEGFantagonist, e.g., anti-VEGF monotherapy. In one embodiment, a subject isanti-VEGF resistant if the subject was previously administered with aVEGF antagonist, e.g., anti-VEGF monotherapy, that did not result in thetreatment or prevention of the ophthalmological disease or disorder;resulted in only a temporary treatment or prevention of theophthalmological disease or disorder and rendered the subject in furtherneed of treatment or prevention of the ophthalmological disease ordisorder; or that resulted in the subject's visual decline and renderedthe subject in further need of treatment or prevention of theophthalmological disease or disorder.

In another embodiment, a subject is anti-VEGF resistant if the subjectwas previously treated or administered with an anti-VEGF treatment,e.g., anti-VEGF monotherapy, and failed to achieve any visual gain orexperienced visual decline. In some embodiments, the subject did notrespond adequately to anti-VEGF treatment. In one embodiment, thesubject was administered the anti-VEGF treatment for one year or longer.In some such embodiments, the subject is in need of treatment for wetAMD.

Accordingly, the present invention provides methods for treating,preventing, or stabilizing wet AMD in a subject, such as a subject whohas failed monotherapy with a VEGF antagonist (e.g., is anti-VEGFresistant, has complement-mediated inflammation, and/or did not respondadequately to anti-VEGF monotherapy). In particular embodiments, themethods comprise determining whether the subject was previouslyadministered or treated with anti-VEGF monotherapy. In certainembodiments, anti-VEGF monotherapy means administration of only one ormore VEGF antagonists. In certain embodiments, anti-VEGF monotherapyincludes the optional administration of other drugs that are not agentsspecifically adapted for treating an ophthalmological disease ordisorder, e.g, wet AMD.

In certain embodiments, the methods and compositions described hereinare useful for treating or preventing an ophthalmological disease ordisorder in a subject that is treatment-naïve. In some embodiments, thesubject is treatment-naïve if the subject was not previously treated forthe ophthalmological disease or disorder. In some embodiments, thesubject is treatment-naïve if the subject was not previouslyadministered or treated with a VEGF antagonist or anti-VEGF monotherapy(“anti-VEGF-treatment-naïve”). In particular embodiments, the methodsfurther comprise determining whether the subject was previously treatedfor the ophthalmological disease or disorder or administered a VEGFantagonist or anti-VEGF monotherapy, e.g., by inquiring of the subjector his or her health care provider, or by reviewing the subject'smedical records. In certain embodiments, anti-VEGF monotherapy meansadministration of only one or more VEGF antagonists. In certainembodiments, anti-VEGF monotherapy includes the optional administrationof other drugs that are not agents specifically adapted for treating anophthalmological disease or disorder, e.g, wet AMD. In some embodiments,the subject is treatment-naïve if the subject was not previously treatedfor AMD (e.g., wet AMD). In some embodiments, the subject istreatment-naïve if the subject was not previously treated, or hasunderwent no previous treatment for AMD (e.g., wet AMD) in either eye.In yet other embodiments, the subject is treatment-naïve if the subjectwas not previously treated, or has underwent no previous treatment, forAMD (e.g., wet AMD; e.g., in either eye) except for one or more oralsupplements of vitamins and minerals. In some embodiments, the subjectis treatment-naïve if the subject was not previously administered atherapeutic agent used for the treatment of AMD (e.g., wet AMD).

In certain embodiments, the subject has complement-mediatedinflammation. In certain embodiments, the subject is anti-VEGF resistantand has complement-mediated inflammation. In certain embodiments, thecomplement-mediated inflammation is present in an eye of the subject. Incertain embodiments, the complement-mediated inflammation results fromprevious administration with anti-VEGF monotherapy. In otherembodiments, the subject has or has been diagnosed withcomplement-mediated inflammation. In still other embodiments, thesubject did not respond adequately to anti-VEGF monotherapy and has orhas been diagnosed with complement-mediated inflammation. In certainembodiments, complement-mediated inflammation is diagnosed in thesubject using a genetic screening method. Such genetic screening methodsare known to those of skill in the art and include, but are not limitedto, screening for mutations in complement genes, such as complementfactor H (CFH), CFI, CFHR5, and MCP, BF, and C2 genes.

In certain embodiments, the methods and compositions described hereinare useful for treating or preventing an ophthalmological disease ordisorder in a subject who is newly diagnosed with the ophthalmologicaldisease or disorder. In some embodiments, the subject is newly diagnosedif the subject was not previously diagnosed for the ophthalmologicaldisease or disorder. In some embodiments, the subject is newly diagnosedwith age-related macular degeneration. In some embodiments, the subjectis newly diagnosed with dry age-related macular degeneration. In someembodiments, the subject is newly diagnosed with wet-type AMD. Inparticular embodiments, the methods further comprise determining whetherthe subject was previously diagnosed for the ophthalmological disease ordisorder, e.g., by inquiring of the subject or his or her health careprovider, or by reviewing the subject's medical records.

In some embodiments of the invention, the methods and compositionsdescribed herein are useful for treating or preventing anophthalmological disease or disorder that is a neovascular disorder. Inother embodiments of the invention, the ophthalmological disease ordisorder results in retinal edema. Illustrative ophthalmologicaldiseases or disorders that can be treated or prevented are describedherein.

Treatment or Prevention of Age-Related Macular Degeneration

In one embodiment, the ophthalmological disease or disorder treated orprevented by any of the methods or compositions described herein isage-related macular degeneration. Vision changes that can be associatedwith macular degeneration include distortions and/or blind spots(scotoma) detected using an Amsler grid, changes in dark adaptation(diagnostic of rod cell health), changes in color interpretation(diagnostic of cone cell health), or a decrease in visual acuity.Examples of age-related macular degeneration are nonneovascular (alsoknown as “dry”) and neovascular (also known as “wet” or “exudative”)macular degeneration.

In one embodiment, the dry age-related macular degeneration isassociated with the formation of drusen. In one embodiment, treating orpreventing dry macular degeneration encompasses treating or preventingan abnormality of the retinal pigment epithelium and/or underlyingvasculature, known as choriocapilaries. Examples of abnormalities of theretinal pigment epithelium include geographic atrophy, non-geographicatrophy, focal hypopigmentation, and focal hyperpigmentation. In anotherembodiment, treating or preventing wet age-related macular degenerationencompasses treating or preventing choroidal neovascularization orpigment epithelial detachment.

In one embodiment, the invention provides methods for treating orpreventing wet age-related macular degeneration. Another aspect of thepresent invention is methods for treating, preventing, or inhibiting achoroidal neovascular complex in a subject, e.g., inhibiting theformation or growth of a choroidal neovascular complex.

In another aspect of the invention, the invention provides methods fortreating or preventing choroidal neovascularization in a subject. Insome embodiments, the choroidal neovascularization is subfovealchoroidal neovascularization. In some embodiments, the subfovealchoroidal neovascularization is due to age-related macular degeneration.In one embodiment, the subfoveal choroidal neovascularization issecondary to exudative type AMD. In other embodiments, the subfovealchoroidal neovascularization is present in subjects who have exudativetype AMD, and in other embodiments, subfoveal choroidalneovascularization is present in subjects who do not have exudative typeAMD. In some embodiments, the subfoveal choroidal neovascularization issecondary to inflammatory, traumatic, myopic, idiopathic or neoplasticafflictions of the macula.

In some embodiments, wet age-related macular degeneration is classifiedaccording to the appearance of its choroidal neovascularization (CNV),into classic, occult or mixed (classic and occult) CNV types, asdetermined by an angiography, known as fluorescence angiography.Classic, occult or mixed (classic and occult) CNV classification can bebased on the time, intensity and level of definition of dye appearance,and leakage from the CNV, as assessed by the fluorescein angiography. Insome embodiments, the subject has classic CNV (e.g., pure classic) ormixed CNV (predominantly or minimally classic CNV). In some embodiments,the subject has occult CNV (e.g., pure occult CNV).

The administration of Antagonist A or another pharmaceuticallyacceptable salt thereof and the VEGF antagonist and/or anti-C5 agent canhave a synergistic effect in treating or preventing classic CNV oroccult CNV. For example, administration of both Antagonist A or anotherpharmaceutically acceptable salt thereof and the VEGF antagonist canimprove visual acuity or stabilize vision to a degree that is greaterthan an additive effect of both Antagonist A or another pharmaceuticallyacceptable salt thereof and the VEGF antagonist. In another example,administration of both Antagonist A or another pharmaceuticallyacceptable salt thereof and the VEGF antagonist can reduce CNV orinhibit the growth of CNV to a greater degree than administration ofAntagonist A or another pharmaceutically acceptable salt thereof or theVEGF antagonist. In some embodiments, administration of both AntagonistA or another pharmaceutically acceptable salt thereof and the VEGFantagonist can reduce CNV in a shorter timeframe or with a lower dosageamount or frequency, as compared to the timeframe or dosage amount withadministration of Antagonist A or another pharmaceutically acceptablesalt thereof or the VEGF antagonist. In some embodiments, administrationof both Antagonist A or another pharmaceutically acceptable salt thereofand the VEGF antagonist can reduce CNV or inhibit the growth of CNV to agreater degree than an additive effect of both Antagonist A or anotherpharmaceutically acceptable salt thereof and the VEGF antagonist. Insome embodiments, administration of both Antagonist A or anotherpharmaceutically acceptable salt thereof and the VEGF antagonist canreduce CNV in a shorter timeframe or with a lower dosage amount orfrequency, as compared to an additive timeframe, dosage amount orfrequency with administration of both Antagonist A or anotherpharmaceutically acceptable salt thereof and the VEGF antagonist.

In one embodiment, the present invention provides methods for treating,preventing, or stabilizing non-exudative type (“dry type”) AMD. In oneembodiment, Antagonist A or another pharmaceutically acceptable saltthereof, an anti-C5 agent, the combination of Antagonist A or anotherpharmaceutically acceptable salt thereof and an anti-C5 agent, or thecombination of an anti-C5 agent and a VEGF antagonist is administered inan amount effective to maintain about the same level of drusen or reducethe level of drusen (e.g., amount, size, number, area and/or morphology)(e.g., size, number, area and/or morphology) as compared to thesubject's drusen level prior to administration of Antagonist A oranother pharmaceutically acceptable salt thereof, the anti-C5 agent, thecombination of Antagonist A or another pharmaceutically acceptable saltthereof and the anti-C5 agent, or or the combination of an anti-C5 agentand a VEGF antagonist, respectively. In a particular embodiment, thelevel of drusen is reduced by at least or about 5%, at least or about10%, at least or about 20%, at least or about 30%, at least or about40%, or at least or about 50%.

In some embodiments, Antagonist A or another pharmaceutically acceptablesalt thereof, an anti-C5 agent, the combination of Antagonist A oranother pharmaceutically acceptable salt thereof and the anti-C5 agent,or the combination of the anti-C5 agent and a VEGF antagonist isadministered in an amount effective to inhibit, slow, or prevent theprogression of non-exudative type AMD to geographic atrophy (GA). GA isan advanced form of non-exudative type AMD. In other embodiments, theAntagonist A or another pharmaceutically acceptable salt thereof and/orthe anti-C5 agent or a pharmaceutically acceptable salt thereof isadministered in an amount effective to reduce the growth or area of a GAlesion over time as compared to that in a subject not receivingAntagonist A or another pharmaceutically acceptable salt thereof and/orthe anti-C5 agent. In other embodiments, the anti-C5 agent or apharmaceutically acceptable salt thereof and a VEGF antagonist isadministered in an amount effective to reduce the growth or area of a GAlesion over time as compared to that in a subject not receiving theanti-C5 agent and/or the VEGF antagonist. In a particular embodiment,the change in area or growth of the geographic atrophy lesion over timeis reduced by at least or about 5%, at least or about 10%, at least orabout 20%, at least or about 30%, at least or about 40%, or at least orabout 50%. Methods of identifying and assessing the size of geographiclesions are known to those of skill in the art and includeautofluorescence imaging and optical coherence tomography.

In particular embodiments, a subject in whom non-exudative AMD convertsto exudative AMD, e.g., when new blood vessels invade the overlyingretina, is treated. The present invention further provides methods fortreating, preventing, or stabilizing drusen retinopathy secondary tocomplement-mediated immune disorders, including drusen retinopathysecondary to membranoproliferative glomerulonephritis type II disease.In some embodiments, Antagonist A or another pharmaceutically acceptablesalt thereof and/or an anti-C5 agent and/or a VEGF antagonist isadministered in an amount effective to reduce retinal drusen in subjectshaving or having been diagnosed with membranoproliferativeglomerulonephritis type II disease or exudative-type AMD as compared tothe level of retinal drusen prior to administration of Antagonist A oranother pharmaceutically acceptable salt thereof and/or an anti-C5 agentand/or a VEGF antagonist. In certain embodiments, the level of drusen isreduced by at least or about 5%, at least or about 10%, at least orabout 20%, at least or about 30%, at least or about 40%, or at least orabout 50%.

In one embodiment, the ophthalmological disease or disorder ispolypoidal choroidal vasculopathy (PCV), a variant of wet AMD.

Treatment or Prevention of a Condition Associated with ChoroidalNeovascularization

In one embodiment, the ophthalmological disease or disorder is acondition associated with choroidal neovascularization. Examples ofconditions associated with choroidal neovascularization include adegenerative, inflammatory, traumatic or idiopathic condition. Treatingor preventing a degenerative disorder associated with choroidalneovascularization also encompasses treating or preventing aheredodegerative disorder. Examples of heredodegenerative disordersinclude vitelliform macular dystrophy, fundus flavimaculatus and opticnerve head drusen. Examples of degenerative conditions associated withchoroidal neovascularization include myopic degeneration or angioidstreaks. In some embodiments, treating or preventing an inflammatorydisorder associated with choroidal neovascularization encompassestreating or preventing ocular histoplasmosis syndrome, multifocalchoroiditis, serpininous choroiditis, toxoplasmosis, toxocariasis,rubella, Vogt-Koyanagi-Harada syndrome, Behcet syndrome or sympatheticophthalmia. In some embodiments, treating or preventing a traumaticdisorder associated with choroidal neovascularization encompassestreating or preventing choroidal rupture or a traumatic condition causedby intense photocoagulation.

Treatment or Prevention of Proliferative Retinopathy

One particular aspect of the invention provides methods and compositionsfor treating or preventing proliferative vitreoretinopathy (PVR). Insome embodiments, the PVR is a moderate form. In other embodiments, thePVR is a severe form. In some embodiments, the PVR is a recurrent form.In one embodiment, the subject with PVR also has or had retinaldetachment, or the subject has PVR associated with retinal detachment,or PVR related scarring (e.g., scarring resulting from PVR, e.g.,retinal scarring). In some embodiments, the PVR is characterized basedon the configuration of the retina and the location of the scar tissue,such as in shown in Table 2 (See Lean J, et al. Classification ofproliferative vitreoretinopathy used in the silicone study. The Siliconestudy group. Ophthalmology 1989; 96:765-771). Any of these categories ortypes of PVR can be treated or prevented according to the presentinvention.

TABLE 2 Classification of PVR Type Type of Location Summary of no.contraction of PVR Clinical Signs 1 Focal Posterior Starfold 2 DiffusePosterior Confluent irregular retinal folds in posterior retina;remainder of retina drawn posteriorly; optic disc may not be visible 3Sub-retinal Posterior “Napkin ring” around disc or “clothesline”elevation of retina 4 Circum- Anterior Irregular retinal folds in theanterior ferential retina; series of radial folds more posteriorly;peripheral retina within vitreous base stretched inward 5 Perpen-Anterior Smooth circumferential fold of dicular retina at insertion ofposterior hyaloid 6 Anterior Anterior Circumferential fold of retina atinsertion of posterior hyaloid pulled forward; trough of peripheralretina anteriorly; ciliary processes stretched with possible hypotony;iris retracted

The present methods for treating PVR can further comprise administeringanother agent useful for treating PVR, such as a corticosteriod;antineoplastic drug, such as 5-fluorouracil; colchicine; retinoid;heparin; epidermal growth factor receptor (EGFR) inhibitor, such asgefitinib or erlotinib.

Another aspect of the invention is methods for treating or preventing aproliferative retinopathy, such as one related to PVR (e.g., treating orpreventing an ocular manifestation of a proliferative retinopathy), suchas proliferative diabetic retinopathy, sickle cell retinopathy, posttraumatic retinopathy, hyperviscosity syndromes, Aortic arch syndromes,ocular ischemic syndromes, carotid-cavernous fistula, multiplesclerosis, retinal vasculitis, systemic lupus erythematosus,arteriolitis with SS-A autoantibody, acute multifocal hemorrhagicvasculitis, vasculitis resulting from infection, vasculitis resultingfrom Behcet's disease, sarcoidosis, coagulopathies, sicklinghemoglobinopathies, AC and C-β thalassemia, small vessel hyalinosis,incontinentia pigmenti, Eales' disease, branch retinal artery or veinocclusion, frosted branch angiitis, idiopathic retinal vasculitis,aneurysms, neuroretinitis, retinal embolization, retinopathy ofprematurity, Uveitis, pars planitis, acute retinal necrosis, birdshotretinochoroidopathy, long-standing retinal detachment, choroidalmelanoma, radiation retinopathy, familial exudative vitreoretinopathy,inherited retinal venous beading, retinoschisis, retinitis pigmentosa,or autosomal dominant vitreoretinochoroidopathy.

Another aspect of the invention is methods for treating or preventing adisease or condition that is a cause that results in proliferativeretinopathy or PVR. In one embodiment, post-retinal detachment (e.g.,that causes or results in PVR) is treated or prevented. In anotherembodiment, proliferative diabetic retinopathy (e.g., that causes orresults in PVR) or sickle-cell retinopathy (e.g., that causes or resultsin PVR), as well as scarring caused by one or more of these disorders istreated or prevented.

Treatment or Prevention of Glaucoma

In one embodiment, the opthalmological disease or disorder is glaucoma.In one embodiment the glaucoma is open angle glaucoma, primary openangle glaucoma, secondary open angle glaucoma, closed angle glaucoma,glaucoma that is associated with diabetes, glaucoma that is associatedwith diabetic retinopathy, angle closure glaucoma, narrow angle glaucomaor acute glaucoma.

Treatment or Prevention of a Neoplasm

In one embodiment, the ophthalmological disease or disorder is aneoplasm. Examples of neoplams include an eyelid tumor, a conjunctivaltumor, a choroidal tumor, an iris tumor, an optic nerve tumor, a retinaltumor, an infiltrative intraocular tumor or an orbital tumor. Examplesof an eyelid tumor include basal cell carcinoma, squamous carcinoma,sebaceous carcinoma, malignant melanoma, capillary hemangioma,hydrocystoma, nevus or seborrheic keratosis. Examples of a conjunctivaltumor include conjunctival Kaposi's sarcoma, squamous carcinoma,intraepithelial neoplasia of the conjunctiva, epibular dermoid, lymphomaof the conjunctiva, melanoma, pingueculum, or pterygium. Examples of achoroidal tumor include choroidal nevus, choroidal hemangioma,metastatic choroidal tumor, choroidal osteoma, choroidal melanoma,ciliary body melanoma or nevus of Ota. Examples of an iris tumor includeanterior uveal metastasis, iris cyst, iris melanocytoma, iris melanoma,or pearl cyst of the iris. Examples of an optic nerve tumor includeoptic nerve melanocytoma, optic nerve sheath meningioma, choroidalmelanoma affecting the optic nerve, or circumpapillary metastasis withoptic neuropathy. Examples of a retinal tumor include retinal pigmentepithelial (RPE) hypertrophy, RPE adenoma, RPE carcinoma,retinoblastoma, or hamartoma of the RPE. In some embodiments, thepresent invention provides methods for inhibiting retinal pigmentepithelium (RPE) or glial cells, such as inhibiting the migration of RPEor glial cells. Examples of an infiltrative intraocular tumor includechronic lymphocytic leukemia, infiltrative choroidopathy, or intraocularlymphoma. Examples of an orbital tumor include adenoid cystic carcinomaof the lacrimal gland, cavernous hemangioma of the orbit, lymphangiomaof the orbit, orbital mucocele, orbital pseudotumor, orbitalrhabdomyosarcoma, periocular hemangioma of childhood, or sclerosingorbital psuedotumor.

Another aspect of the invention is methods for treating or preventingvon Hippel-Lindau (VHL) disease (e.g., treating or preventing visualloss associated VHL disease). In some embodiments, VHL disease ischaracterized by tumors. The tumors may be malignant or benign. Inanother embodiment, a benign or malignant tumor in the eye (e.g., oculartumor) or a cyst (e.g., an ocular cyst), associated with VHL is treatedor prevented. In some embodiments, the tumors are hemangioblastomas. Insome embodiments, the tumors are von Hippel angioma or retinal capillaryhemangiomas (e.g., juxtapapillary hemangioma).

In some embodiments, the subject with VHL disease has a deficiency ofthe protein “pVHL.”

In some embodiments, the VHL disease is severe (e.g., a subject withsevere VHL disease has a lesion that cannot be effectively treated witha non-pharmacologic modality (e.g., laser or or cryotherapy), forexample, as the lesion resides over or adjacent to a significant neuralstructure (e.g., optic nerve, macula, papillomacular bundle) that can bedamaged with laser or cryotherapy).

In some embodiments, the methods for treating or preventing VHL diseasecomprise treating an ocular or non-ocular manifestation (e.g., benign ormalignant neoplasm or cyst of the kidney, adrenal gland, pancreas,brain, spinal cord, inner ear, epididymis, or broad ligament) of VHL.

In some embodiments, the subjected being treated has a family history ofVHL disease or one or more of retinal capillary hemangioma (RCH), spinalor cerebellar hemangioblastoma, pheochromocytoma, multiple pancreaticcysts, epididymal or broad ligament cystadenoma, multiple renal cysts,and renal cell carcinoma. In some embodiments, the subject has one ormore RCH, spinal and cerebellar hemangioblastoma, pheochromocytoma,multiple pancreatic cysts, epididymal or broad ligament cystadenomas,multiple renal cysts, or renal cell carcinoma before the age of 60years. In some embodiments, the subject has two or morehemangioblastomas of the retina or brain or a single hemangioblastoma inassociation with a visceral manifestation, such as kidney or pancreaticcysts; renal cell carcinoma; adrenal or extra-adrenal pheochromocytomas;endolymphatic sac tumors; papillary cystadenomas of the epididymis orbroad ligament; or neuroendocrine tumors of the pancreas. In someembodiments, the subject has a disease-causing germline mutation in theVHL gene.

In some embodiments, the subject has RCH that exhibit activity, such asassociated intra- or sub-retinal exudation or lipid deposition (whichmay reflect ongoing vascular incompetence and is not reflective ofresidual changes following previous treatment or secondary to coexistentretinal traction); increased size of the tumor compared to a previoustime point as assessed by fundus photography or fluorescein angiography(FA); associated intra-, sub-, or pre-retinal hemorrhage not secondaryto previous treatment, as assessed by fundus photography or FA;appearance of new feeder vessels or greater dilation or tortuosity ofexisting feeder vessels compared to a previous time point; and/orvitreous cell or haze indicative of vitreous exudation, in the absenceof other ocular features potentially responsible for such findings. Insome embodiments, the subject has RCH that is not readily treatableusing cryotherapy or thermal laser because of its size, posteriorlocation, poor previous response to conventional therapy, or otherfactors.

In some embodiments, methods or compositions of the invention are usedto treat or prevent a complication of VHL, visual dysfunction (e.g.,from VHL), or a fibrous complication of VHL (e.g., fibrous meningioma).In certain embodiments, the methods or compositions of the presentinvention are used to treat a manifestation of VHL as vascularproliferation that comprises fine, superficial, juxtapapillary vesselsthat are often associated with fibrovascular proliferation andepiretinal membrane formation.

Treatment or Prevention of Scarring or Fibrosis

Another aspect the invention provides methods for treating, inhibitingor preventing scarring or fibrosis (e.g., scarring or fibrosis is underthe macular region of the retina). In some embodiments, the scarring isa fibrovascular scar (e.g., in the retina). In some embodiments, thefibrosis is hepatic, pulmonary or renal fibrosis. In some embodiments,the fibrosis is ocular fibrosis. In some embodiments, the fibrosis issub-retinal fibrosis (e.g., associated with neovascular AMD). In someembodiments, the sub-retinal fibrosis is not associated with neovascularAMD. In some embodiments, the fibrosis is subfoveal fibrosis. In someembodiments, the subfoveal fibrosis is with retinal atrophy. In someembodiments, subfoveal fibrosis or sub-retinal fibrosis develops afteradministration of a VEGF antagonist, e.g., anti-VEGF monotherapy.

In some embodiments, the scarring results from glaucoma surgery, orfollows glaucoma surgery, such as trabeculectomy, filtering surgery(such as partial thickness filtering surgery), glaucoma filteringprocedures, minimally invasive glaucoma surgery, glaucoma valve implantsurgery, glaucoma seton surgery, glaucoma tube shunt placement, glaucomastent placement, or combined cataract and glaucoma surgery. In someembodiments, the methods of the present invention are useful to treat orprevent scarring relating to or resulting from glaucoma surgery (e.g.,that can result in scar related proliferation). In some embodiments, thescarring is sub-retinal scarring. In some embodiments, the scarring issub-retinal scarring that occurs following choroidal neovascularregression.

In particular embodiments, methods for treating, inhibiting orpreventing sub-retinal fibrosis (e.g., reducing the formation ofsub-retinal fibrosis) comprise administering to a subject in needthereof an effective amount of Antagonist A or another pharmaceuticallyacceptable salt thereof and a VEGF antagonist. In some embodiments, thesubject has or is diagnosed with AMD (e.g., wet AMD). In someembodiments, the subject has or is diagnosed with advanced wet AMD.

Treatment or Prevention of Other Ophthalmological Diseases and Disorders

In certain embodiments, the ophthalmological disease or disorder is acataract (e.g., age-related cataract), diabetic macula edema, maculartelangiectasia (e.g., type 1 or 2 macular telangiectasia), atrophicmacular degeneration, chorioretinopathy (e.g., central serouschorioretinopathy), retinal inflammatory vasculopathy, pathologicalretinal angiogenesis, age-related maculopathy, retinoblastoma,Pseudoxanthoma elasticum, a vitreoretinal disease, choroidal sub-retinalneovascularization, central serous chorioretinopathy, ischemicretinopathy, hypertensive retinopathy or diabetic retinopathy (e.g.,nonproliferative or proliferative diabetic retinopathy, such as macularedema or macular ischemia), retinopathy of prematurity (e.g., associatedwith abnormal growth of blood vessels in the vascular bed supporting thedeveloping retina), venous occlusive disease (e.g., a retinal veinocclusion, branch retinal vein occlusion or central retinal veinocclusion), arterial occlusive disease (e.g., branch retinal arteryocclusion (BRAO), central retinal artery occlusion or ocular ischemicsyndrome), central serous chorioretinopathy (CSC), cystoid macular edema(CME) (e.g., affecting the central retina or macula, or after cataractsurgery), retinal telangiectasia (e.g., characterized by dilation andtortuosity of retinal vessels and formation of multiple aneurysms,idiopathic JXT, Leber's miliary aneurysms, or Coats' disease), arterialmacroaneurysm, retinal angiomatosis, radiation-induced retinopathy(RIRP), or rubeosis iridis (e.g., associated with the formation ofneovascular glaucoma, diabetic retinopathy, central retinal veinocclusion, ocular ischemic syndrome, or chronic retinal detachment).

In other embodiments, the ophthalmological disease or disorder is sicklecell disease (SCD), anemia, or sickle cell retinopathy (e.g.,non-neovascular or non-proliferative ocular manifestations). In someembodiments, vaso-occlusive phenomena or hemolysis associated with SCDis treated or prevented. In some embodiments, ocular manifestations ofSCD include vascular occlusions in the conjunctiva, iris, retina, orchoroid. Non-neovascular or non-proliferative ocular manifestations caninclude conjunctival vascular occlusions which transform smooth vesselsinto comma-shaped fragments, iris atrophy, retinal “salmon patch”hemorrhages, retinal pigmentary changes and other abnormalities of theretinal vasculature, macula, choroid, and optic disc. In someembodiments, neovascularization or the proliferative ocularmanifestation involves the growth of abnormal vascular fronds which canlead to vitreous hemorrhage, retinal detachment, epiretinal membranes,resulting in vision loss. In some embodiments, the methods furthercomprise performing another treatment, such as diathermy, cryotherapy,laser photocoagulation or surgery (e.g., vitrectomy).

In one embodiment, the ophthalmological disease or disorder is acondition associated with peripheral retinal neovascularization.Examples of conditions associated with peripheral retinalneovascularization include ischemic vascular disease, inflammatorydisease with possible ischemia, incontinentia pigmenti, retinitispigmentosa, retinoschisis or chronic retinal detachment.

Examples of ischemic vascular disease include proliferative diabeticretinopathy, branch retinal vein occlusion, branch retinal arteriolarocclusion, carotid cavernous fistula, sickling hemoglobinopathy,non-sickling hemoglobinopathy, IRVAN syndrome (retinal vasculiticdisorder characterized by idiopathic retinal vasculitis, an aneurysm,and neuroretinitis), retinal embolization, retinopathy of prematurity,familial exudative vitreoretinopathy, hyperviscosity syndrome, aorticarch syndrome or Eales disease. Examples of sickling hemoglobinopathyinclude SS hemoglobinopathy and SC hemoglobinopathy. Examples ofnon-sickling hemoglobinopathy include AC hemoglobinopathy and AShemoglobinopathy. Examples of hyperviscosity syndrome include leukemia,Waldenstrom macroglobulinemia, multiple myeloma, polycythemia ormyeloproliferative disorder.

In some embodiments, treating or preventing an inflammatory disease withpossible ischemia encompasses treating or preventing retinal vasculitisassociated with systemic disease, retinal vasculitis associated with aninfectious agent, uveitis or birdshot retinopathy. Examples of systemicdiseases include systemic lupus erythematosis, Behcet's disease,inflammatory bowel disease, sarcoidosis, multiple sclerosis, Wegener'sgranulomatosis and polyarteritis nodosa. Examples of infectious agentsinclude a bacterial agent that is the causative agent for syphilis,tuberculosis, Lyme disease or cat-scratch disease, a virus such asherpesvirus, or a parasite such as Toxocara canis or Toxoplasma gondii.Examples of uveitis include pars planitis or Fuchs uveitis syndrome.

Compositions for Therapeutic or Prophylactic Administration

Antagonist A or another pharmaceutically acceptable salt thereof, VEGFantagonists, or anti-C5 agents can be administered as a component of acomposition that further comprises a pharmaceutically acceptable carrieror vehicle, e.g., a pharmaceutical composition. In certain embodiments,each therapeutic agent is administered to the subject in a separatecomposition. However, in other embodiments, two or more therapeuticagents may be administered to the subject in the same composition. Inone embodiment, a composition of the invention comprises an effectiveamount of Antagonist A or another pharmaceutically acceptable saltthereof, a VEGF antagonist, and/or an anti-C5 agent and apharmaceutically acceptable carrier or vehicle. In another embodiment, acomposition comprising Antagonist A or another pharmaceuticallyacceptable salt thereof and another composition comprising a VEGFantagonist are administered. In some embodiments, another compositioncomprising an anti-C5 agent is administered. In some embodiments, acomposition comprising Antagonist A or another pharmaceuticallyacceptable salt thereof and a VEGF antagonist is administered. In someembodiments, another composition comprising an anti-C5 agent is alsoadministered.

Administration of each antagonist may be by any suitable means thatresults in an amount of Antagonist A or another pharmaceuticallyacceptable salt thereof, VEGF antagonist, and/or anti-C5 agent that iseffective for the treatment or prevention of an ophthalmological diseaseor disorder. Each antagonist, for example, can be admixed with asuitable carrier substance, and is generally present in an amount of1-95% by weight of the total weight of the composition. The compositionmay be provided in a dosage form that is suitable for ophthalmic, oral,parenteral (e.g., intravenous, intramuscular, subcutaneous), rectal,transdermal, nasal, or inhalant administration. In one embodiment, thecomposition is in a form that is suitable for injection directly in theeye. The composition may be in form of, e.g., tablets, capsules, pills,powders, granulates, suspensions, emulsions, solutions, gels includinghydrogels, pastes, ointments, creams, plasters, delivery devices,suppositories, enemas, injectables, implants, sprays, drops or aerosols.The compositions comprising one or more antagonists can be formulatedaccording to conventional pharmaceutical practice (see, e.g., Remington:The Science and Practice of Pharmacy, (20th ed.) ed. A. R. Gennaro,2000, Lippincott Williams & Wilkins, Philadelphia, Pa. and Encyclopediaof Pharmaceutical Technology, eds., J. Swarbrick and J. C. Boylan,1988-2002, Marcel Dekker, New York).

The compositions are, in one useful aspect, administered parenterally(e.g., by intramuscular, intraperitoneal, intravenous, intraocular,intravitreal, retro-bulbar, subconjunctival, subtenon or subcutaneousinjection or implant) or systemically. Formulations for parenteral orsystemic administration include sterile aqueous or non-aqueoussolutions, suspensions, or emulsions. A variety of aqueous carriers canbe used, e.g., water, buffered water, saline, and the like. Examples ofother suitable vehicles include polypropylene glycol, polyethyleneglycol, vegetable oils, gelatin, hydrogels, hydrogenated naphalenes, andinjectable organic esters, such as ethyl oleate. Such formulations mayalso contain auxiliary substances, such as preserving, wetting,buffering, emulsifying, and/or dispersing agents. Biocompatible,biodegradable lactide polymer, lactide/glycolide copolymer, orpolyoxyethylene-polyoxypropylene copolymers may be used to control therelease of the active ingredients.

Alternatively, the compositions can be administered by oral ingestion.Compositions intended for oral use can be prepared in solid or liquidforms, according to any method known to the art for the manufacture ofpharmaceutical compositions.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. Generally, these pharmaceuticalpreparations contain active ingredients admixed with non-toxicpharmaceutically acceptable excipients. These include, for example,inert diluents, such as calcium carbonate, sodium carbonate, lactose,sucrose, glucose, mannitol, cellulose, starch, calcium phosphate, sodiumphosphate, kaolin and the like. Binding agents, buffering agents, and/orlubricating agents (e.g., magnesium stearate) may also be used. Tabletsand pills can additionally be prepared with enteric coatings. Thecompositions may optionally contain sweetening, flavoring, coloring,perfuming, and preserving agents in order to provide a more palatablepreparation.

Compositions useful for ophthalmic use include tablets comprising one ormore antagonists in admixture with a pharmaceutically acceptableexcipient. These excipients may be, for example, inert diluents orfillers (e.g., sucrose and sorbitol), lubricating agents, glidants, andantiadhesives (e.g., magnesium stearate, zinc stearate, stearic acid,silicas, hydrogenated vegetable oils, or talc).

The antagonists of the present invention may be admixed in a tablet orother vehicle, or may be partitioned. In one example, one antagonist iscontained on the inside of the tablet, and the other antagonist is onthe outside, such that a substantial portion of the other antagonist isreleased prior to the release of the contained antagonist. If desired,antagonists in a tablet form may be administered using a drug deliverydevice (see below).

For example, compositions of the present invention may be administeredintraocularly by intravitreal injection into the eye as well as bysubconjunctival and subtenon injections. Other routes of administrationinclude transcleral, retrobulbar, intraperitoneal, intramuscular, andintravenous. Alternatively, compositions can be administered using adrug delivery device or an intraocular implant (see below).

In one embodiment, Antagonist A or another pharmaceutically acceptablesalt thereof or VEGF antagonist (e.g., ranibizumab, bevacizumab,aflibercept, pegaptanib sodium, or ESBA1008) is administeredintravitreally with a 30-gauge or 27-gauge needle. In some embodiments,a 0.5 inch needle is used. In one embodiment, Antagonist A or anotherpharmaceutically acceptable salt thereof is administered intravitreallywith a 30-gauge 0.5 inch needle and a VEGF antagonist (e.g.,ranibizumab, bevacizumab, aflibercept, pegaptanib sodium, or ESBA1008)is administered intravitreally with a 27-gauge needle. In someembodiments, 50 μL (1.5 mg in 0.05 mL) of Antagonist A or anotherpharmaceutically acceptable salt thereof is administered intravitreallywith a 30-gauge 0.5 inch needle and 50 μL of a VEGF antagonist (e.g.,0.5 mg of ranibizumab, 1.25 mg of bevacizuamb, or 2.0 mg of aflibercept)is administered intravitreally with a 27-gauge needle.

Liquid dosage forms for oral administration can include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and soft gelatincapsules. These forms can contain inert diluents commonly used in theart, such as water or an oil medium, and can also include adjuvants,such as wetting agents, emulsifying agents, and suspending agents.

In some instances, the compositions can also be administered topically,for example, by patch or by direct application to a region, such as theepidermis or the eye, susceptible to or affected by a neovasculardisorder, or by iontophoresis.

In one embodiment, the compositions can comprise one or morepharmaceutically acceptable excipients. In one embodiment, excipientsfor compositions that comprise an antagonist include, but are notlimited to, buffering agents, nonionic surfactants, preservatives,tonicity agents, sugars, amino acids, and pH-adjusting agents. Suitablebuffering agents include, but are not limited to, monobasic sodiumphosphate, dibasic sodium phosphate, and sodium acetate. Suitablenonionic surfactants include, but are not limited to, polyoxyethylenesorbitan fatty acid esters such as polysorbate 20 and polysorbate 80.Suitable preservatives include, but are not limited to, benzyl alcohol.Suitable tonicity agents include, but are not limited to sodiumchloride, mannitol, and sorbitol. Suitable sugars include, but are notlimited to, α,α-trehalose. Suitable amino acids include, but are notlimited to glycine and histidine. Suitable pH-adjusting agents include,but are not limited to, hydrochloric acid, acetic acid, and sodiumhydroxide. In one embodiment, the pH-adjusting agent or agents arepresent in an amount effective to provide a pH of about 3 to about 8,about 4 to about 7, about 5 to about 6, about 6 to about 7, or about 7to about 7.5. In one embodiment, the compositions do not comprise apreservative. In another embodiment, the composition does not comprisean antimicrobial agent. In another embodiment, the composition does notcomprise a bacteriostat. Suitable excipients for a VEGF antagonist alsoinclude those described in U.S. Pat. No. 7,365,166, the contents ofwhich are herein incorporated by reference in their entirety.

In one embodiment, the composition is in the form of an aqueous solutionthat is suitable for injection. In one embodiment, a composition is inthe form of an aqueous solution that is suitable for injection. In oneembodiment, a composition comprises Antagonist A or anotherpharmaceutically acceptable salt thereof, a buffering agent, apH-adjusting agent, and water for injection. In another embodiment, acomposition comprises Antagonist A or another pharmaceuticallyacceptable salt thereof, monobasic sodium phosphate, dibasic sodiumphosphate, sodium chloride, hydrochloride acid, and sodium hydroxide.

In one embodiment, the composition comprises a VEGF antagonist, abuffering agent, a sugar, a nonionic surfactant, and water forinjection. In another embodiment, the composition comprises a VEGFantagonist, monobasic sodium phosphate, dibasic sodium phosphate,α,α-trehalose dehydrate, and polysorbate 20. In one embodiment, thecomposition comprises a VEGF antagonist, a buffering agent, apH-adjusting agent, a tonicity agent, and water that is suitable forinjection. In another embodiment, the composition comprises a VEGFantagonist, monobasic sodium phosphate, dibasic sodium phosphate, sodiumchloride, hydrochloric acid, and sodium hydroxide. In one embodiment,the VEGF antagonist is a pegylated anti-VEGF aptamer, e.g., pegaptanibsodium

In another embodiment, the VEGF antagonist is ranibizumab, bevacizumab,aflibercept or ESBA1008. This invention provides the pharmaceuticallyacceptable salts of the antagonists. An antagonist of the presentinvention can possess a sufficiently basic functional group, which canreact with any of a number of inorganic and organic acids, to form apharmaceutically acceptable salt. A pharmaceutically-acceptable acidaddition salt is formed from a pharmaceutically-acceptable acid, as iswell known in the art. Such salts include the pharmaceuticallyacceptable salts listed in Journal of Pharmaceutical Science, 66, 2-19(1977) and The Handbook of Pharmaceutical Salts; Properties, Selection,and Use. P. H. Stahl and C. G. Wermuth (ED.s), Verlag, Zurich(Switzerland) 2002, which are hereby incorporated by reference in theirentirety.

Examples of a pharmaceutically acceptable salts include sulfate,citrate, acetate, oxalate, chloride, bromide, iodide, nitrate,bisulfate, phosphate, acid phosphate, isonicotinate, lactate,salicylate, acid citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucaronate, saccharate, formate, benzoate, glutamate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate,camphorsulfonate, pamoate, phenylacetate, trifluoroacetate, acrylate,chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate,methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, isobutyrate,phenylbutyrate, α-hydroxybutyrate, butyne-1,4-dicarboxylate,hexyne-1,4-dicarboxylate, caprate, caprylate, cinnamate, glycollate,heptanoate, hippurate, malate, hydroxymaleate, malonate, mandelate,mesylate, nicotinate, phthalate, teraphthalate, propiolate, propionate,phenylpropionate, sebacate, suberate, p-bromobenzenesulfonate,chlorobenzenesulfonate, ethylsulfonate, 2-hydroxyethylsulfonate,methylsulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate,naphthalene-1,5-sulfonate, xylenesulfonate, and tartarate salts. Theterm “pharmaceutically acceptable salt” includes a hydrate of a compoundof the invention and also refers to a salt of an antagonist of thepresent invention having an acidic functional group, such as acarboxylic acid functional group or a hydrogen phosphate functionalgroup, and a base. Suitable bases include, but are not limited to,hydroxides of alkali metals such as sodium, potassium, and lithium;hydroxides of alkaline earth metal such as calcium and magnesium;hydroxides of other metals, such as aluminum and zinc; ammonia, andorganic amines, such as unsubstituted or hydroxy-substituted mono-, di-,or tri-alkylamines, dicyclohexylamine; tributyl amine; pyridine;N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, ortris-(2-OH-lower alkylamines), such as mono-; bis-, ortris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, ortris-(hydroxymethyl)methylamine, N,N-di-lower alkyl-N-(hydroxyl-loweralkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine ortri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such asarginine, lysine, and the like. In one embodiment, the pharmaceuticallyacceptable salt is a sodium salt. In another embodiment, thepharmaceutically acceptable salt is a persodium salt.

The present invention further provides comprising Antagonist A oranother pharmaceutically acceptable salt thereof. In one embodiment, thepresent compositions comprise about 30.0 mg of Antagonist A or anotherpharmaceutically acceptable salt thereof, about 0.3 mg of monobasicsodium phosphate monohydrate, about 2.1 mg of dibasic sodium phosphateheptahydrate and about 9.0 mg of sodium chloride per about 1 mL. In someembodiments, hydrochloric acid and/or sodium hydroxide are present asneeded to adjust the pH of the composition. In some embodiments, the pHis about pH 5.5 to about pH 7.5 or about pH 6.0.

In some embodiments, the compositions comprise about 3% (w/v) ofAntagonist A or another pharmaceutically acceptable salt thereof, about0.03% (w/v) of monobasic sodium phosphate monohydrate, about 0.2% (w/v)of dibasic sodium phosphate heptahydrate, about 0.9% (w/v) of sodiumchloride and about 95.9% (w/v) of water. In some embodiments,hydrochloric acid and/or sodium hydroxide are present as needed toadjust the pH of the composition. In some embodiments, the pH is aboutpH 5.5 to about pH 7.5 or about pH 6.0.

In certain embodiments, the concentration of Antagonist A or anotherpharmaceutically acceptable salt thereof, a VEGF antagonist (e.g.,ranibizumab, bevacizumab, aflibercept, ESBA1008 or pegaptanib sodium),and/or an anti-C5 agent (e.g., ARC1905 or a pharmaceutically acceptablesalt thereof) in a composition is about 0.002 mg/mL to about 50 mg/mL.In some embodiments, the concentration of Antagonist A or anotherpharmaceutically acceptable salt thereof, a VEGF antagonist (e.g.,ranibizumab, bevacizumab, aflibercept, ESBA1008 or pegaptanib sodium),and/or an anti-C5 agent (e.g., ARC1905 or a pharmaceutically acceptablesalt thereof) in a composition is less than or about 100 mg/mL, lessthan about 50 mg/mL, less than about 40 mg/mL, less than about 30 mg/mL,less than about 25 mg/mL, less than about 20 mg/mL, less than about 15mg/mL, less than about 10 mg/mL, or less than about 5 mg/mL. In certainembodiments, the concentration of Antagonist A or anotherpharmaceutically acceptable salt thereof, a VEGF antagonist (e.g.,ranibizumab, bevacizumab, aflibercept, ESBA1008 or pegaptanib sodium),and/or an anti-C5 agent (e.g., ARC1905 or a pharmaceutically acceptablesalt thereof) in a composition is about 0.3 mg/mL to about 100 mg/mL,about 0.3 mg/mL to about 50 mg/mL, about 0.3 mg/mL to about 40 mg/mL,about 0.3 mg/mL to about 30 mg/mL, about 0.3 to about 25 mg/mL, about0.3 mg/mL to about 20 mg/mL, about 0.3 mg/mL to about 15 mg/mL, about0.3 mg/mL to about 10 mg/mL, about 1 mg/mL to about 100 mg/mL, about 1mg/mL to about 50 mg/mL, about 1 mg/mL to about 40 mg/mL, about 1 mg/mLto about 30 mg/mL, about 1 mg/mL to about 25 mg/mL, about 1 mg/mL toabout 20 mg/mL, about 1 mg/mL to about 15 mg/mL, about 1 mg/mL to about10 mg/mL, about 1 mg/mL to about 5 mg/mL, about 5 mg/mL to about 100mg/mL, or about 5 mg/mL to about 50 mg/mL.

In certain embodiments, methods of the invention comprise administeringAntagonist A and optionally one or both of a VEGF antagonist and ananti-C5 agent as a component of a pharmaceutical composition. In oneembodiment, the present invention provides compositions comprising aneffective amount of: (a) Antagonist A or another pharmaceuticallyacceptable salt thereof; and (b) a VEGF antagonist or a pharmaceuticallyacceptable salt thereof. In certain embodiments, the compositionsfurther comprise an effective amount of an anti-C5 agent or apharmaceutically acceptable salt thereof. In some embodiments, thecompositions stabilize one or more of the Antagonist A or anotherpharmaceutically acceptable salt thereof, the VEGF antagonist, and theanti-C5 agent. In certain embodiments, the Antagonist A or anotherpharmaceutically acceptable salt thereof, the VEGF antagonist and/or theanti-C5 agent does not adversely affect the activity of the other activeagent(s) present in the composition. In particular embodiments, at leastabout 90% of one or more of the active agents in the composition, e.g.,Antagonist A or another pharmaceutically acceptable salt thereof, VEGFantagonist, or anti-C5 agent, is chemically stable when the compositionis stored at a temperature of from about 2.0° C. to about 8.0° C. for atleast about twelve weeks.

In particular embodiments, Antagonist A or another pharmaceuticallyacceptable salt thereof, the VEGF antagonist or the anti-C5 agent ischemically stable when it shows no sign of decomposition or modificationresulting in formation of a new chemical entity. In particularembodiments, Antagonist A or another pharmaceutically acceptable saltthereof, the VEGF antagonist or the anti-C5 agent is chemically stablewhen at least about 50%, at least about 60%, at least about 70%, atleast about 80%, at least about 90%, a least about 95%, or at leastabout 99% of Antagonist A or another pharmaceutically acceptable saltthereof, the VEGF antagonist or the anti-C5 agent shows no sign ofdecomposition or modification resulting in formation of a new chemicalentity, e.g., when stored at a temperature of from about 2.0° C. toabout 8.0° C. for at least about twelve weeks.

In certain embodiments, the Antagonist A or another pharmaceuticallyacceptable salt thereof does not adversely affect the activity of theVEGF antagonist (e.g., ranibizumab, bevacizumab, aflibercept, pegaptanibsodium, or ESBA1008) or the ARC1905 or a pharmaceutically acceptablesalt thereof. In certain embodiments, the VEGF antagonist (e.g.,ranibizumab, bevacizumab, aflibercept, pegaptanib sodium, or ESBA1008)does not adversely affect the activity of the Antagonist A or anotherpharmaceutically acceptable salt thereof, or ARC1905 or apharmaceutically acceptable salt thereof. In certain embodiments,ARC1905 or a pharmaceutically acceptable salt thereof does not adverselyaffect the activity of the Antagonist A or another pharmaceuticallyacceptable salt thereof, or the VEGF antagonist (e.g., ranibizumab,bevacizumab, aflibercept, pegaptanib sodium, or ESBA1008).

In particular embodiments, the compositions comprise Antagonist A oranother pharmaceutically acceptable salt thereof; and ranibizumab,bevacizumab, aflibercept, pegaptanib sodium or ESBA1008, or apharmaceutically acceptable salt thereof, and the compositions arephysically or chemically stable with respect to both active agents at aparticular pH or suitable for parenteral administration. In particularembodiments, the compositions comprise Antagonist A or anotherpharmaceutically acceptable salt thereof; ranibizumab, bevacizumab,aflibercept, pegaptanib sodium or ESBA1008 or a pharmaceuticallyacceptable salt thereof; and ARC1905 or a pharmaceutically acceptablesalt thereof, and the compositions are physically or chemically stablewith respect to all active agents at a particular pH or suitable forparenteral administration. In particular embodiments, a composition isphysically stable if at least about 50%, at least about 60%, at leastabout 70%, at least about 80%, at least about 90%, at least about 95%,or at least about 99% of all active agents, i.e., the Antagonist A oranother pharmaceutically acceptable salt thereof, the VEGF antagonist,and the anti-C5 agent (when present) present in the composition show nosign of aggregation, precipitation or denaturation upon visualexamination of color or clarity, or as measured by UV light scatteringor by size exclusion chromatography (SEC) or differential scanningcalorimetry (DSC).

In particular embodiments, the compositions of the invention areconsidered physically stable if after storage the average number ofparticles detected does not exceed about 50 particles/mL, where theparticles have a diameter >about 10 μm and does not exceed 5particles/mL, where the particles have a diameter >25 μm, as measured bythe Light Obscuration Particle Count Test described in (788) ParticulateMatter in Injections, Revised Bulletin, Official Oct. 1, 2011, TheUnited States Pharmacopeial Convention.

In particular embodiments, the compositions are considered physicallystable if after storage the average number of particles detected doesnot exceed 50 particles/mL, where the particles have a diameter >10 μm;does not exceed 5 particles/mL, where the particles have a diameter >25μm; and does not exceed 2 particles/mL, where the particles have adiameter >50 μm, as measured by the microscopic method particle counttest described in (788) Particulate Matter in Injections, RevisedBulletin, Official Oct. 1, 2011, The United States PharmacopeialConvention.

In particular embodiments, the compositions comprise Antagonist A oranother pharmaceutically acceptable salt thereof, a VEGF antagonist(e.g., ranibizumab, bevacizumab, aflibercept, ESBA1008 or pegaptanibsodium) and, optionally, an anti-C5 agent (e.g., ARC1905 or apharmaceutically acceptable salt thereof) and are chemically stable forat least eight weeks or at least twelve weeks at 25° C. or for at leasttwelve weeks or at least sixteen weeks or at least 24 weeks at 4° C. Inparticular embodiments, at least 80% of each of Antagonist A or anotherpharmaceutically acceptable salt thereof, VEGF antagonist, and anti-C5agent (if present) show no sign of decomposition or modificationresulting in formation of a new chemical entity under at least one ofthese conditions.

In particular embodiments, compositions comprise the following: (1)Antagonist A or another pharmaceutically acceptable salt thereof; (2) aVEGF antagonist; optionally, (3) an anti-C5 agent; (4) a buffer;optionally, (5) a tonicity modifier; and, optionally, (6) a surfactant.In specific embodiments of such compositions, the buffer is an acetate,phosphate, Tris or histidine buffer, or a mixture thereof; the tonicitymodifier is sodium chloride, mannitol, sorbitol, or trehalose, or amixture thereof; and the surfactant is polysorbate 20. In variousembodiments, Antagonist A or another pharmaceutically acceptable saltthereof is present in compositions of the invention at a concentrationof about 0.1 mg/mL to about 200 mg/mL; and the VEGF antagonist ispresent at a concentration of about 0.1 mg/mL to about 200 mg/mL. Whenpresent, the anti-C5 agent is present at a concentration of about 0.1mg/mL to about 200 mg/mL. The buffer is present at a concentration ofabout 1 mM to about 200 mM; the tonicity modifier is present at aconcentration of about 10 mM to about 200 mM (sodium chloride), about 1%to about 10% (w/v) (sorbitol), or about 1% to about 20% (w/v)(trehalose); and the surfactant, when present, is present at aconcentration of about 0.005% to about 0.05% or a concentration of about0.001% to about 0.05%.

In particular embodiments, the ratio of the concentration (mass ofAntagonist A or another pharmaceutically acceptable salt thereof lessthat of its —R group/volume of composition) of Antagonist A or anotherpharmaceutically acceptable salt thereof to the concentration(mass/volume of composition) of the VEGF antagonist (e.g., ranibizumab,bevacizumab, aflibercept, pegaptanib sodium, or ESBA1008), ARC1905, or apharmaceutically acceptable salt thereof, present in the composition isless than, or less than or equal to, 25.0, less than, or less than orequal to, 10.0, less than, or less than or equal to, 9.0, less than, orless than or equal to, 8.0, less than, or less than or equal to, 7.0,less than, or less than or equal to, 6.0, less than, or less than orequal to, 5.0, less than, or less than or equal to, 4.0, less than, orless than or equal to, 3.0, less than, or less than or equal to, 2.0 orless than, or less than or equal to, 1.0. Antagonist A's —R group isdepicted in FIG. 1. In particular embodiments, the ratio of theconcentration (mass of Antagonist A or another pharmaceuticallyacceptable salt thereof less that of its —R group/volume of composition)of Antagonist A or another pharmaceutically acceptable salt thereof tothe concentration (mass/volume of composition) of the VEGF antagonist(e.g., ranibizumab, bevacizumab, aflibercept, pegaptanib sodium, orESBA1008), ARC1905, or a pharmaceutically acceptable salt thereof,present in the composition is in the range of about 1 to about 10, about2 to about 5, about 3 about 4, or about 5. In certain embodiments, thecompositions comprise Antagonist A or another pharmaceuticallyacceptable salt thereof, a VEGF antagonist (e.g., ranibizumab,bevacizumab, aflibercept, pegaptanib sodium, or ESBA1008), and ARC1905or a pharmaceutically acceptable salt thereof.

In one particular embodiment, the compositions comprise Antagonist A oranother pharmaceutically acceptable salt thereof, a VEGF antagonist(e.g., ranibizumab, bevacizumab, aflibercept, ESBA1008, or pegaptanibsodium), and, optionally, an anti-C5 agent (e.g., ARC1905 or apharmaceutically acceptable salt thereof), wherein the ratio of theconcentration of PDGF antagonist to the concentration of VEGF antagonist(and/or anti-C5 agent) is less than 2; and the compositions furthercomprise sodium chloride at a concentration of about 10 mM to about 200mM, histidine at a concentration of about 1 mM to about 100 mM, andpolysorbate (e.g., polysorbate 20) at a concentration of about 0.005% toabout 0.05%, where the pH of the composition is about 5.5 to about 7.0.

In certain embodiments, the compositions comprise one or more of atonicity modifier, a surfactant, and a buffer suitable to achieve ormaintain the particular pH or be suitable for parenteral administration.Appropriate buffers include those described herein as well as othersknown in the art, such as, e.g., Good's buffers, e.g., IVIES.

In certain embodiments, the compositions comprise Antagonist A oranother pharmaceutically acceptable salt thereof, a VEGF antagonist(e.g., ranibizumab, bevacizumab, aflibercept, ESBA1008 or pegaptanibsodium), and a tonicity modifier that is sorbitol or sodium chloride, ormixtures thereof. In certain embodiments, the compositions furthercomprise an anti-C5 agent (e.g., ARC1905 or a pharmaceuticallyacceptable salt thereof). In particular embodiments, the tonicitymodifier is sorbitol, and the pH of the composition is about 5.0 toabout 8.0, about 5.0 to about 7.0, about 6.0 or about 7.0. In particularembodiments, the tonicity modifier is sodium chloride, and the pH of thecomposition is about 5.0 to about 8.0, about 5.0 to about 7.0, about 5.5to about 7.5, about 6.0 to about 8.0, about 8.0, about 7.0, or about6.0. In certain embodiments, the tonicity modifier is sorbitol at about1% to about 10% (w/v), or about 1% (w/v), about 2% (w/v), about 3%(w/v), about 4% (w/v), about 5% (w/v), about 6% (w/v), about 7% (w/v),about 8% (w/v), about 9% (w/v), or about 10% (w/v). In particularembodiments, the tonicity modifier is sodium chloride at a concentrationof about 10 mM to about 200 mM, about 50 mM to 200 mM, about 75 mM toabout 200 mM, about 50 mM to about 150 mM, about 100 mM, about 110 mM,about 120 mM, about 130 mM about 140 mM or about 150 mM. In oneembodiment, the tonicity modifier is sodium chloride at a concentrationof about 130 mM. In other embodiments, the tonicity modifier is sodiumchloride at a concentration of about 75 mM or about 120 mM. With respectto tonicity modifier concentration, “mM” refers to milimoles of thetonicity modifier per liter of composition.

In certain embodiments, the compositions comprise Antagonist A oranother pharmaceutically acceptable salt thereof, a VEGF antagonist(e.g., ranibizumab, bevacizumab, aflibercept, ESBA1008 or pegaptanibsodium), and a buffer capable of achieving or maintaining the pH of thecomposition within a desired range. In certain embodiments, thecompositions further comprise an anti-C5 agent (e.g., ARC1905 or apharmaceutically acceptable salt thereof). In certain embodiments, thecompositions comprise histidine (e.g., L-histidine or a pharmaceuticallyacceptable salt thereof) or phosphate as a buffer, e.g., sodiumphosphate, potassium phosphate, or both. In certain embodiments, thebuffer is present at a concentration of about 1 mM to about 200 mM,about 1 mM to about 150 mM, about 1 mM to about 20 mM, about 1 mM toabout 10 mM, about 2 mM to about 100 mM, about 2 mM to about 20 mM,about 5 mM to about 20 mM, or about 10 mM. In particular embodiments,the pH of the buffered composition is about 5.0 to about 8.0, about 5.0to about 7.0, about 5.5 to about 7.5, about 5.5 to about 7.0, or about6.0. In one embodiment, the buffered composition has a pH of about 5.5to about 7.0. In certain embodiments, the buffer comprises histidine ata concentration of about 1 mM to about 200 mM, about 1 mM to about 150mM, about 2 mM to about 100 mM, about 5 mM to about 20 mM, or about 10mM, and the buffered composition has a pH of about 5.5 to about 7.0, orabout 6.0. In one particular embodiment, the buffer comprises histidineat a concentration of about 10 mM and the pH of the histidine-bufferedcomposition is about 6.0. With respect to buffer concentration, “mM”refers to millimoles of buffer (e.g., histidine) per liter ofcomposition.

In certain embodiments, the compositions comprise Antagonist A oranother pharmaceutically acceptable salt thereof, a VEGF antagonist(e.g., ranibizumab, bevacizumab, aflibercept, ESBA1008 or pegaptanibsodium), and a buffer that comprises phosphate, alone or in combinationwith histidine. In certain embodiments, the compositions furthercomprise an anti-C5 agent (e.g., ARC1905 or a pharmaceuticallyacceptable salt thereof). The phosphate buffer may be, e.g., a sodiumphosphate or potassium phosphate buffer. In certain embodiments, thebuffer comprises phosphate at a concentration of about 1 mM to about 200mM, about 1 mM to about 50 mM, about 2 mM to about 200 mM, about 2 mM toabout 50 mM, about 5 mM to about 200 mM, about 5 mM to about 100 mM,about 5 mM to about 50 mM, about 10 mM to about 150 mM, about 10 mM toabout 100 mM, about 5 mM, about 10 mM, about 25 mM, or about 50 mM. Inparticular embodiments, the pH of the buffered composition is about 5.0to about 8.0, about 6.0 to about 8.0, about 5.5 to about 7.5, about 5.5to about 7.0, about 6.0, about 7.0, or about 8.0. In one embodiment, thebuffer comprises phosphate, and the buffered composition has a pH ofabout 6.0 to about 8.0. In certain embodiments, the buffer comprisesphosphate at a concentration of about 5 mM to about 200 mM, about 5 mMto about 150 mM, about 5 mM to about 100 mM, about 5 mM, about 8 mM,about 10 mM, about 25 mM, or about 50 mM, and the buffered compositionhas a pH of about 5.5 to about 7.5, about 5.5 to about 7.0, or about6.0. In one particular embodiment, the buffer comprises phosphate at aconcentration of about 10 mM, and the buffered composition has a pH ofabout 6.2.

In certain embodiments, the compositions comprise Antagonist A oranother pharmaceutically acceptable salt thereof), a VEGF antagonist(e.g., ranibizumab, bevacizumab, aflibercept, ESBA1008 or pegaptanibsodium), and a surfactant. In certain embodiments, the compositionsfurther comprise an anti-C5 agent (e.g., ARC1905 or a pharmaceuticallyacceptable salt thereof). In particular embodiments, the surfactant ispolysorbate 20 at a concentration of about 0.001% (w/v) to about 0.05%(w/v), about 0.002% (w/v) to about 0.05% (w/v), about 0.005% (w/v) toabout 0.05% (w/v), about 0.01% (w/v) to about 0.05% (w/v), or about0.02% (w/v).

In one embodiment, the compositions comprise Antagonist A or anotherpharmaceutically acceptable salt thereof, a VEGF antagonist (e.g.,ranibizumab, bevacizumab, aflibercept, ESBA1008 or pegaptanib sodium),histidine, and NaCl. In certain embodiments, the compositions furthercomprise an anti-C5 agent (e.g., ARC1905 or a pharmaceuticallyacceptable salt thereof). The composition may further comprisepolysorbate.

In certain embodiments, the compositions comprise an effective amountof: (a) about 0.3 mg/mL to about 30 mg/mL of Antagonist A or anotherpharmaceutically acceptable salt thereof; (b) about 0.5 mg/mL to about20 mg/mL of a VEGF antagonist (e.g., ranibizumab, bevacizumab,aflibercept, ESBA1008 or pegaptanib sodium); and one or both of: (c) abuffer capable of achieving or maintaining the pH of the compositions atabout pH 5.0 to about pH 8.0; and (d) a tonicity modifier. In certainembodiments, the compositions further comprise (e) about 0.3 mg/mL toabout 30 mg/mL of an anti-C5 agent (e.g., ARC1905 or a pharmaceuticallyacceptable salt thereof). In certain embodiments, the buffer is about 1mM to about 20 mM L-histidine or about 1 mM to about 20 mM sodiumphosphate, and the tonicity modifier is about 10 mM to about 200 mMNaCl, about 1% to about 20% (w/v) sorbitol, or about 1% to about 20%(w/v) trehalose. In particular embodiments, the compositions furthercomprise: (f) about 0.001% (w/v) to about 0.05% (w/v) surfactant.

In certain embodiments, the compositions comprise: (a) about 0.3 mg/mLto about 30 mg/mL of Antagonist A or another pharmaceutically acceptablesalt thereof; and (b) about 0.5 mg/mL to about 20 mg/mL of a VEGFantagonist (e.g., ranibizumab, bevacizumab, aflibercept, ESBA1008 orpegaptanib sodium). In certain embodiments, the compositions furthercomprise (c) about 0.3 mg/mL to about 30 mg/mL of an anti-C5 agent(e.g., ARC1905 or a pharmaceutically acceptable salt thereof). Incertain embodiments, any of these the compositions further comprise oneor both of: (d) about 1 mM to about 20 mM L-histidine; and (e) about 10mM to about 200 mM NaCl. In further embodiments, the compositionsfurther comprise: (f) about 0.001% (w/v) to about 0.05% (w/v)surfactant, which is optionally polysorbate. In a particular embodiment,the compositions comprise: (a) about 0.3 mg/mL to about 30 mg/mL ofAntagonist A or another pharmaceutically acceptable salt thereof; (b)about 0.5 mg/mL to about 20 mg/mL of a VEGF antagonist (e.g.,ranibizumab, bevacizumab, aflibercept, ESBA1008 or pegaptanib sodium);(c) about 1 mM to about 20 mM L-histidine; and (d) about 10 mM to about200 mM NaCl, wherein the pH of the compositions is about pH 5.0 to aboutpH 7.0. In certain embodiments, the compositions further comprise (e)about 0.3 mg/mL to about 30 mg/mL of an anti-C5 agent (e.g., ARC1905 ora pharmaceutically acceptable salt thereof). In certain embodiments, thecompositions further comprise: (f) about 0.01% (w/v) polysorbate 20.

In certain embodiments, compositions comprise: (a) about 1.0 mg/mL toabout 100 mg/mL, or about 5.0 mg/mL to about 50 mg/mL of Antagonist A oranother pharmaceutically acceptable salt thereof); and (b) about 1.0mg/mL to about 50 mg/mL of a VEGF antagonist (e.g., ranibizumab,bevacizumab, aflibercept, ESBA1008 or pegaptanib sodium). In certainembodiments, the compositions further comprise (c) about 1.0 mg/mL toabout 100 mg/mL of an anti-C5 agent (e.g., ARC1905 or a pharmaceuticallyacceptable salt thereof). In other embodiments, any of the compositionsfurther comprise one or both of (d) about 1 mM to about 20 mML-histidine; and (e) about 10 mM to about 200 mM NaCl. In furtherembodiments, any of the compositions further comprise: (f) about 0.001%(w/v) to about 0.05% (w/v) surfactant, which is optionally polysorbate.

In certain embodiments, compositions comprise: (a) about 0.3 mg/mL toabout 30 mg/mL of Antagonist A or another pharmaceutically acceptablesalt thereof); (b) about 0.5 mg/mL to about 20 mg/mL of a VEGFantagonist (e.g., ranibizumab, bevacizumab, aflibercept, ESBA1008 orpegaptanib sodium); and one or both of (c) a buffer capable of achievingor maintaining the pH of the composition to about pH 5.0 to about pH8.0; and (d) a tonicity modifier. In certain embodiments, thecompositions further comprise about 0.3 mg/mL to about 30 mg/mL of ananti-C5 agent (e.g., ARC1905 or a pharmaceutically acceptable saltthereof). In particular embodiments, the buffer, where present, is about1 mM to about 20 mM L-histidine or about 1 mM to about 20 mM sodiumphosphate; and the tonicity modifier, where present, is about 10 mM toabout 200 mM NaCl, about 1% to about 20% (w/v) sorbitol, or about 1% toabout 20% (w/v) trehalose. In certain embodiments, the buffer is about 1mM to about 20 mM L-histidine; and the tonicity modifier is about 10 mMto about 200 mM NaCl, wherein the pH of the compositions is about pH 5.0to about pH 7.0.

Any of the compositions can also comprise a surfactant, e.g., about0.001% (w/v) to about 0.05% (w/v) surfactant.

In certain embodiments the compositions comprise: (a) about 3 mg/mL toabout 90 mg/mL Antagonist A or another pharmaceutically acceptable saltthereof; (b) about 1.0 mg/mL to about 30 mg/mL of a VEGF antagonist(e.g., ranibizumab, bevacizumab, aflibercept, ESBA1008 or pegaptanibsodium); and one or both of (c) a buffer capable of achieving ormaintaining the pH of the compositions to about pH 5.0 to about pH 8.0;and (d) a tonicity modifier. In certain embodiments, any of thecompositions further comprises (e) about 3 mg/mL to about 90 mg/mL of ananti-C5 agent (e.g., ARC1905 or a pharmaceutically acceptable saltthereof). In particular embodiments, the buffer, where present,comprises about 1 mM to about 100 mM sodium phosphate or about 1.0 mM toabout 10 mM histidine.HCl; and the tonicity modifier, where present, isabout 0.5% (w/v) to about 10% (w/v) trehalose.

In certain embodiments, a composition of the invention comprises: (a)about 0.3 mg/mL to about 30 mg/mL Antagonist A or anotherpharmaceutically acceptable salt thereof; (b) about 0.5 mg/mL to about20 mg/mL ranibizumab or a pharmaceutically acceptable salt thereof; andone or both of: (c) a buffer capable of achieving or maintaining the pHof the composition at about pH 5.0 to about pH 8.0; and (d) a tonicitymodifier. In certain embodiments, the buffer is about 1 mM to about 20mM L-histidine or about 1 mM to about 20 mM sodium phosphate, and thetonicity modifier is about 10 mM to about 200 mM NaCl, about 1% to about20% (w/v) sorbitol, or about 1% to about 20% (w/v) trehalose. Inparticular embodiments, the composition of the invention furthercomprises: (e) about 0.001% (w/v) to about 0.05% (w/v) surfactant. Inparticular embodiments, the composition further comprises: (f) ananti-C5 agent, another PDGF antagonist, or another VEGF antagonist. Inparticular embodiments, the anti-C5 agent is ARC 186, ARC 187, orARC1905, and the other VEGF antagonist is bevacizumab or aflibercept.

In certain embodiments, a composition of the invention comprises: (a)about 0.3 mg/mL to about 30 mg/mL Antagonist A or anotherpharmaceutically acceptable salt thereof; and (b) about 0.5 mg/mL toabout 25 mg/mL bevacizumab or a pharmaceutically acceptable saltthereof; and one or both of: (c) a buffer capable of achieving ormaintaining the pH of the composition at about pH 5.0 to about pH 8.0;and (d) a tonicity modifier. In certain embodiments, the buffer is about5 mM to about 200 mM sodium phosphate or about 5 mM to about 200 mMTris.HCl, and the tonicity modifier is about 10 mM to about 200 mM NaCl,about 1% to about 20% (w/v) sorbitol, or about 1% to about 20% (w/v)trehalose. In particular embodiments, the composition of the inventionfurther comprises: (e) about 0.001% (w/v) to about 0.05% (w/v)surfactant. In particular embodiments, the composition furthercomprises: (f) an anti-C5 agent, another PDGF antagonist, and/or anotherVEGF antagonist. In particular embodiments, the anti-C5 agent is ARC186,ARC187, or ARC1905, and the other VEGF antagonist is ranibizumab oraflibercept.

In certain embodiments, a composition of the invention comprises: (a)about 0.3 mg/mL to about 30 mg/mL Antagonist A or anotherpharmaceutically acceptable salt thereof; (b) about 5 mg/mL to about 40mg/mL aflibercept or a pharmaceutically acceptable salt thereof; and oneor more of: (c) a buffer capable of achieving or maintaining the pH ofthe composition at about pH 5.0 to about pH 8.0; (d) a tonicitymodifier; and (e) 0 to about 10% (w/v) sucrose. In certain embodiments,the buffer is about 5 mM to about 50 mM phosphate, and the tonicitymodifier is about 10 mM to about 200 mM NaCl. In particular embodiments,the composition of the invention further comprises: (f) about 0.001%(w/v) to about 0.05% (w/v) surfactant. In particular embodiments, thecomposition further comprises: (g) an anti-C5 agent, another PDGFantagonist, and/or another VEGF antagonist. In particular embodiments,the anti-C5 agent is ARC186, ARC187, or ARC1905, and the other VEGFantagonist is ranibizumab or bevacizumab.

In certain embodiments, a composition of the invention comprises: (a)about 3 mg/mL to about 90 mg/mL Antagonist A or another pharmaceuticallyacceptable salt thereof; (b) about 1.0 mg/mL to about 30 mg/mLranibizumab or a pharmaceutically acceptable salt thereof; and one orboth of: (c) a buffer capable of achieving or maintaining the pH of thecomposition at about pH 5.0 to about pH 8.0; and (d) a tonicitymodifier. In certain embodiments, the buffer comprises about 1 mM toabout 100 mM sodium phosphate or about 1.0 mM to about 10 mMhistidine.HCl, and the tonicity modifier is about 0.5% (w/v) to about10% (w/v) trehalose. In particular embodiments, the composition furthercomprises: (e) an anti-C5 agent, another PDGF antagonist, and/or anotherVEGF antagonist. In particular embodiments, the anti-C5 agent is ARC186,ARC187, or ARC1905, and the other VEGF antagonist is bevacizumab oraflibercept.

Illustrative compositions include F1-F31, as described in Tables 3 and4. Illustrative compositions are also described in PCT ApplicationPublication No. WO2013/181495. Any of these compositions may furthercomprise an anti-C5 agent, such as ARC1905 or a pharmaceuticallyacceptable salt thereof.

TABLE 3 Composition Matrix for Illustrative Antagonist A: RanibizumabCompositions [Ant. A] [ran] Polysorbate Comp. Buffer pH TonicityModifier (mg/mL) (mg/mL) 20 (% w/v) F1 10 mM Sodium Phosphate 7.3 150 mMNaCl 3 0 0%   F2 10 mM Sodium Acetate 5.0 5% (w/v) Sorbitol 3 5 0.01% F310 mM Sodium Acetate 5.0 130 mM NaCl 3 5 0.01% F4 10 mM Histidine•HCl5.5 10% (w/v) Trehalose 0 5 0.01% F5 10 mM Histidine•HCl 6.0 5% (w/v)Sorbitol 3 5 0.01% F6 10 mM Histidine•HCl 6.0 130 mM NaCl 3 5 0.01% F710 mM Sodium Phosphate 7.0 5% (w/v) Sorbitol 3 5 0.01% F8 10 mM SodiumPhosphate 7.0 130 mM NaCl 3 5 0.01% F9 10 mM Tris•HCl 8.0 5% (w/v)Sorbitol 3 5 0.01% F10 10 mM Tris•HCl 8.0 130 mM NaCl 3 5 0.01% F11 5 mMSodium Phosphate + 6.5 75 mM NaCl + 3 5  0.005% 5 mM Histidine 5% (w/v)Trehalose F27 10 mM Sodium Phosphate 7.3 150 mM NaC1 30 0 0%   F28 10 mMHistidine•HCl 5.5 10% (w/v) Trehalose 0 10 0.01% F29 10 mM Histidine•HCl5.5 10% (w/v) Trehalose 0 40 0.01% F30 5 mM Sodium Phosphate + 75 mMNaCl + 5% 15 5  0.005% 5 mM Histidine•HCl (w/v) Trehalose F31 8 mMSodium Phosphate + 120 mM NaCl + 2% 24 8  0.002% 2 mM Histidine•HCl(w/v) Trehalose “Ant. A” is Antagonist A; “ran.” is ranibizumab

TABLE 4 Composition Matrix for Illustrative Antagonist A: BevacizumabCompositions Antagonist A Concentration Bevacizumab Tonicity (mg/mL,oligo Concentration Comp. Buffer pH Modifier wt.) (mg/mL) Surfactant F1210 mM 7.3 150 mM Sodium 30 0.0 0% Phosphate Chloride F13 50 mM 4 5%(w/v) 3 12.5 0.02% Acetate Sorbitol Polysorbate 20 F14 50 mM 4 130 mMSodium 3 12.5 0.02% Acetate Chloride Polysorbate 20 F15 50 mM 5 5% (w/v)3 12.5 0.02% Acetate Sorbitol Polysorbate 20 F16 50 mM 5 130 mM Sodium 312.5 0.02% Acetate Chloride Polysorbate 20 F17 50 mM 6 5% (w/v) 3 12.50.02% Phosphate Sorbitol Polysorbate 20 F18 50 mM 6.2 6% (w/v) 0 12.50.02% Phosphate Trehalose Polysorbate 20 F19 50 mM 6 130 mM Sodium 312.5 0.02% Phosphate Chloride Polysorbate 20 F20 50 mM 7 5% (w/v) 3 12.50.02% Phosphate Sorbitol Polysorbate 20 F21 50 mM 7 130 mM Sodium 3 12.50.02% Phosphate Chloride Polysorbate 20 F22 50 mM 8 5% (w/v) 3 12.50.02% Tris Sorbitol Polysorbate 20 F23 50 mM 8 130 mM Sodium 3 12.50.02% Tris Chloride Polysorbate 20 F24 30 mM 6.3 75 mM sodium 15 12.50.02% Phosphate Chloride +3% Polysorbate 20 (w/v) Trehalose F25 10 mM7.3 150 mM Sodium 3 0.0 0% Phosphate Chloride F26 30 mM 6.3 75 mM sodium3 12.5 0.02% Phosphate Chloride + 3% Polysorbate 20 (w/v) Trehalose

Administration and Dosage

The methods or compositions according to the invention can beadministered alone or in conjunction with another therapy and can beprovided at home, a doctor's office, a clinic, a hospital's outpatientdepartment, or a hospital. Treatment can begin at a hospital so that thedoctor can observe the therapy's effects closely and make anyadjustments that are needed. The duration of the administration candepend on the type of ophthalmological disease or disorder being treatedor prevented, the age and condition of the subject, the stage and typeof the subject's disease or disorder, and how the subject responds tothe treatment. Additionally, a subject having a greater risk ofdeveloping an ophthalmological disease or disorder (e.g., a diabeticpatient) can receive treatment to inhibit or delay the onset ofsymptoms. In one embodiment, the present methods or compositions allowfor the administration of a relatively lower dose of each antagonist.

The dosage and frequency of administration of each antagonist can becontrolled independently. For example, one antagonist can beadministered three times per day, while the other antagonist can beadministered once per day. Administration can be performed in on-and-offcycles that include rest periods so that the subject's body has a chanceto recover from a side effect, if any. The antagonists can also bepresent in the same composition.

In other embodiments, Antagonist A or another pharmaceuticallyacceptable salt thereof and optionally, a VEGF antagonist and/or anti-C5agent are administered prior to, during, and/or after another treatment.In one embodiment, Antagonist A or another pharmaceutically acceptablesalt thereof and the VEGF antagonist and/or anti-C5 agent areadministered concurrently, such as in a co-formulation, prior to,during, and/or after the other treatment. In other embodiments,Antagonist A or another pharmaceutically acceptable salt thereof and theVEGF antagonist are administered sequentially, prior to, during, and/orafter the other treatment. In some embodiments, Antagonist A or anotherpharmaceutically acceptable salt thereof is administered prior to theadministration of the VEGF antagonist. In other embodiments, AntagonistA or another pharmaceutically acceptable salt thereof is administeredsubsequent to the administration of the VEGF antagonist. In someembodiments, the other treatment is performing surgery. Examples ofother treatment include pneumatic retinopexy, laser retinopexy, scleralbuckling, and pars plana vitrectomy (PPV), laser photocoagulation, orcryotherapy.

Administration of a composition disclosed herein with performing anothertreatment can improve retinal attachment success, improve visual acuity,reduce choroidal neovascularization or stabilize vision to a degree thatis greater than performing the other treatment alone. For example, insome embodiments, the administration of both Antagonist A or anotherpharmaceutically acceptable salt thereof with performing anothertreatment can improve retinal attachment success, improve visual acuity,or stabilize vision to a degree that is greater than an additive effectof both Antagonist A or another pharmaceutically acceptable salt thereofwith performing the other treatment. In some embodiments, thesynergistic effect is in reducing the size or growth of a tumor (e.g.,in treating or preventing VHL disease, retinal capillary hemangioma, orvon Hippel angioma). In some embodiments, the synergistic effect isreducing or inhibiting scarring or fibrosis (e.g., ocular scarring offibrosis, such as subretinal fibrosis).

Administration of both Antagonist A or another pharmaceuticallyacceptable salt thereof and the VEGF antagonist can improve retinalattachment success, improve visual acuity, or stabilize vision to adegree that is greater than administration of Antagonist A or anotherpharmaceutically acceptable salt thereof or the VEGF antagonist. In someembodiments, the administration of Antagonist A or anotherpharmaceutically acceptable salt thereof and the VEGF antagonist canhave a synergistic effect in treating or preventing an ophthalmologicaldisease or disorder. For example, the administration of both AntagonistA or another pharmaceutically acceptable salt thereof and the VEGFantagonist can improve retinal attachment success, improve visualacuity, or stabilize vision to a degree that is greater than an additiveeffect of administering both Antagonist A or another pharmaceuticallyacceptable salt thereof and the VEGF antagonist. In some embodiments,the synergistic effect is in reducing the size or growth of a tumor(e.g., in treating or preventing VHL disease, retinal capillaryhemangioma, or von Hippel angioma). In some embodiments, the synergisticeffect is reducing or inhibiting scarring or fibrosis (e.g., ocularscarring of fibrosis, such as subretinal fibrosis).

In some embodiments, the methods comprise administering Antagonist A oranother pharmaceutically acceptable salt thereof, VEGF antagonist andanti-C5 agent, in which two or more of Antagonist A or anotherpharmaceutically acceptable salt thereof, the VEGF antagonist and theanti-C5 agent are present in the same composition. In certainembodiments, the PDGF antagonist and the VEGF antagonist are present inthe same composition; in certain embodiments, Antagonist A or anotherpharmaceutically acceptable salt thereof and the anti-C5 agent arepresent in the same composition; and in certain embodiments, the VEGFantagonist and the anti-C5 agent are present in the same composition. Insome embodiments, all three of Antagonist A or another pharmaceuticallyacceptable salt thereof, the VEGF antagonist and the anti-C5 agent arepresent in the same composition.

In some embodiments, Antagonist A or another pharmaceutically acceptablesalt thereof, the VEGF antagonist and the anti-C5 agent are administeredsequentially. In one embodiment, Antagonist A or anotherpharmaceutically acceptable salt thereof is administered prior to theVEGF antagonist or the anti-C5 agent. In one embodiment, the VEGFantagonist is administered prior to Antagonist A or anotherpharmaceutically acceptable salt thereof or the anti-C5 agent. In oneembodiment, the anti-C5 agent is administered prior to the VEGFantagonist or Antagonist A or another pharmaceutically acceptable saltthereof. In one embodiment, Antagonist A or another pharmaceuticallyacceptable salt thereof is administered prior to the VEGF antagonist andanti-C5 agent. In one embodiment, the VEGF antagonist is administeredprior to Antagonist A or another pharmaceutically acceptable saltthereof and the -C5 agent. In one embodiment, the anti-C5 agent isadministered prior to the VEGF antagonist and PDGF antagonist.

In certain embodiments, the subject is administered two or more activeagents (e.g., Antagonist A or another pharmaceutically acceptable saltthereof and a VEGF antagonist) in a staggered dosing regimen, whereinone or more of the two or more active agents is administered beforeanother one or more of the two or more active agents is administered tothe subject.

In certain embodiments, the one or more active agent(s) is administeredat least one day before the other one or more active agent(s).Accordingly, in some embodiments the present methods compriseadministering on one or more days Antagonist A or anotherpharmaceutically acceptable salt thereof, one or more VEGF antagonistsor one or more anti-C5 agents.

In one embodiment, the order of administration is: Antagonist A oranother pharmaceutically acceptable salt thereof, followed by VEGFantagonist, followed by anti-C5 agent. In another embodiment, the orderof administration is: Antagonist A or another pharmaceuticallyacceptable salt thereof, followed by anti-C5 agent, followed by VEGFantagonist. In another embodiment, the order of administration is: VEGFantagonist, followed by anti-C5 agent, followed by Antagonist A oranother pharmaceutically acceptable salt thereof. In another embodiment,the order of administration is: VEGF antagonist, followed by AntagonistA or another pharmaceutically acceptable salt thereof, followed byanti-C5 agent. In yet another embodiment the order of administration is:anti-C5 agent, followed by Antagonist A or another pharmaceuticallyacceptable salt thereof, followed by VEGF antagonist. In anotherembodiment the order of administration is: anti-C5 agent, followed byVEGF antagonist, followed by PDGF antagonist.

In some embodiments, the Antagonist A or another pharmaceuticallyacceptable salt thereof and the VEGF antagonist are administeredconcurrently, and the anti-C5 agent is administered prior to orsubsequent to administration of the PDGF antagonist and VEGF antagonist.In some embodiments, Antagonist A or another pharmaceutically acceptablesalt thereof and the anti-C5 agent are administered concurrently, andthe VEGF antagonist is administered prior to or subsequent toadministration of Antagonist A or another pharmaceutically acceptablesalt thereof and the VEGF antagonist. In some embodiments, the VEGFantagonist and anti-C5 agent are administered concurrently, andAntagonist A or another pharmaceutically acceptable salt thereof isadministered prior to or subsequent to administration of the anti-C5agent and VEGF antagonist.

In other embodiments, the order of administration is: Antagonist A oranother pharmaceutically acceptable salt thereof, followed by VEGFantagonist and anti-C5 agent, wherein the VEGF antagonist and anti-C5agent are present in the same composition. In another embodiment, theorder of administration is: VEGF antagonist, followed by anti-C5 agentand Antagonist A or another pharmaceutically acceptable salt thereof,wherein the anti-C5 agent and PDGF antagonist are present in the samecomposition. In yet another embodiment the order of administration is:anti-C5 agent, followed by Antagonist A or another pharmaceuticallyacceptable salt thereof and VEGF antagonist, wherein the PDGF antagonistand VEGF antagonist are present in the same composition.

In still other embodiments, the order of administration is: Antagonist Aor another pharmaceutically acceptable salt thereof and VEGF antagonist,wherein Antagonist A or another pharmaceutically acceptable salt thereofand the VEGF antagonist are present in the same composition, followed byanti-C5 agent. In another embodiment, the order of administration is:Antagonist A or another pharmaceutically acceptable salt thereof andanti-C5 agent, wherein Antagonist A or another pharmaceuticallyacceptable salt thereof and the anti-C5 agent are present in the samecomposition, followed by VEGF antagonist. In another embodiment, theorder of administration is: VEGF antagonist and anti-C5 agent, whereinthe VEGF antagonist and anti-C5 agent are present in the samecomposition, followed by Antagonist A or another pharmaceuticallyacceptable salt thereof.

For example, Antagonist A or another pharmaceutically acceptable saltthereof can be administered prior to or subsequent to administration ofa VEGF antagonist and/or an anti-C5 agent; a VEGF antagonist can beadministered prior to or subsequent to administration of Antagonist A oranother pharmaceutically acceptable salt thereof and/or anti-C5 agent;or an anti-C5 agent can be administered prior to or subsequent toadministration of Antagonist A or another pharmaceutically acceptablesalt thereof and/or a VEGF antagonist.

In some embodiments, the present methods comprise administering a firstagent prior to administering a second agent. In some embodiments, thepresent methods comprise administering a first agent prior toadministering a second agent and administering the second agent prior toadministering a third agent.

In some embodiments, the present methods comprise concurrentlyadministering a first agent and a second agent. In some embodiments, thepresent methods comprise concurrently administering a first agent and asecond agent prior to administering a third agent.

In some embodiments, the present methods comprise administering a firstagent prior to concurrently administering a second agent and thirdagent.

In some embodiments, the present methods comprise concurrentlyadministering a first agent, a second agent and a third agent.

Illustrative groups of first agent, second agent and third agent are setforth below in Tables 5 and 6.

TABLE 5 Group First Agent Second Agent Third Agent A Antagonist A VEGFantagonist Anti-C5 Agent or another pharmaceutically acceptable saltthereof B Antagonist A Anti-C5 Agent VEGF antagonist or anotherpharmaceutically acceptable salt thereof C VEGF Antagonist A or anotherAnti-C5 Agent antagonist pharmaceutically acceptable salt thereof D VEGFAnti-C5 Agent Antagonist A antagonist or another pharmaceuticallyacceptable salt thereof E Anti-C5 Agent Antagonist A or another VEGFantagonist pharmaceutically acceptable salt thereof F Anti-C5 Agent VEGFantagonist Antagonist A or another pharmaceutically acceptable saltthereof

TABLE 6 Group First Agent Second Agent Third Agent A Antagonist Aranibizumab ARC1905 B Antagonist A bevacizumab ARC1905 C Antagonist Aaflibercept ARC1905 D Antagonist A pegaptanib sodium ARC1905 EAntagonist A ESBA1008 ARC1905 F Antagonist A ARC1905 ranibizumab GAntagonist A ARC1905 bevacizumab H Antagonist A ARC1905 aflibercept IAntagonist A ARC1905 pegaptanib sodium J Antagonist A ARC1905 ESBA1008 Kranibizumab Antagonist A ARC1905 L bevacizumab Antagonist A ARC1905 Maflibercept Antagonist A ARC1905 N pegaptanib sodium Antagonist AARC1905 O ESBA1008 Antagonist A ARC1905 P ranibizumab ARC1905 AntagonistA Q bevacizumab ARC1905 Antagonist A R aflibercept ARC1905 Antagonist AS pegaptanib sodium ARC1905 Antagonist A T ESBA1008 ARC1905 Antagonist AU ARC1905 Antagonist A ranibizumab V ARC1905 Antagonist A bevacizumab WARC1905 Antagonist A aflibercept X ARC1905 Antagonist A pegaptanibsodium Y ARC1905 Antagonist A ESBA1008 Z ARC1905 ranibizumab AntagonistA AA ARC1905 bevacizumab Antagonist A AB ARC1905 aflibercept AntagonistA AC ARC1905 pegaptanib sodium Antagonist A AD ARC1905 ESBA1008Antagonist A

In some embodiments, the present methods comprise administeringAntagonist A or another pharmaceutically acceptable salt thereof and twoor more VEGF antagonists. In some embodiments, the present methodscomprise administering Antagonist A or another pharmaceuticallyacceptable salt thereof and two or more anti-C5 agents. In someembodiments, the present methods comprise administering a VEGFantagonist and two or more anti-C5 agents.

In some embodiments, the present methods comprise administeringAntagonist A or another pharmaceutically acceptable salt thereof priorto administering two or more VEGF antagonists. In some embodiments, thepresent methods comprise administering Antagonist A or anotherpharmaceutically acceptable salt thereof prior to administering a firstVEGF antagonist and administering the first VEGF antagonist prior toadministering a second VEGF antagonist.

In some embodiments, the present methods comprise concurrentlyadministering Antagonist A or another pharmaceutically acceptable saltthereof and a VEGF antagonist. In some embodiments, the present methodscomprise concurrently administering Antagonist A or anotherpharmaceutically acceptable salt thereof and a first VEGF antagonistprior to administering a second VEGF antagonist.

In some embodiments, the present methods comprise administeringAntagonist A or another pharmaceutically acceptable salt thereof priorto concurrently administering a first VEGF antagonist and a second VEGFantagonist.

In some embodiments, the present methods comprise concurrentlyadministering Antagonist A or another pharmaceutically acceptable saltthereof, a first VEGF antagonist and a second VEGF antagonist.

In some embodiments, the present methods comprise administering a VEGFantagonist prior to administering two PDGF antagonists (e.g., AntagonistA or another pharmaceutically acceptable salt thereof and another PDGFantagonist). In some embodiments, the present methods compriseadministering a VEGF antagonist prior to administering a first PDGFantagonist and administering the first PDGF antagonist prior toadministering a second PDGF antagonist.

In some embodiments, the present methods comprise concurrentlyadministering a VEGF antagonist and Antagonist A or anotherpharmaceutically acceptable salt thereof. In some embodiments, thepresent methods comprise concurrently administering a VEGF antagonistand a first PDGF antagonist prior to administering a second PDGFantagonist.

In some embodiments, the present methods comprise administering a VEGFantagonist prior to concurrently administering a first PDGF antagonistand a second PDGF antagonist.

In some embodiments, the present methods comprise concurrentlyadministering a VEGF antagonist, a first PDGF antagonist and a secondPDGF antagonist.

In some embodiments, the present methods comprise administeringAntagonist A or another pharmaceutically acceptable salt thereof priorto administering two or more anti-C5 agents. In some embodiments, thepresent methods comprise administering Antagonist A or anotherpharmaceutically acceptable salt thereof prior to administering a firstanti-C5 agent and administering the first anti-C5 agent prior toadministering a second anti-C5 agent.

In some embodiments, the present methods comprise concurrentlyadministering Antagonist A or another pharmaceutically acceptable saltthereof and an anti-C5 agent. In some embodiments, the present methodscomprise concurrently administering Antagonist A or anotherpharmaceutically acceptable salt thereof and a first anti-C5 agent priorto administering a second anti-C5 agent.

In some embodiments, the present methods comprise administeringAntagonist A or another pharmaceutically acceptable salt thereof priorto concurrently administering a first anti-C5 agent and a second anti-C5agent.

In some embodiments, the present methods comprise concurrentlyadministering Antagonist A or another pharmaceutically acceptable saltthereof, a first anti-C5 agent and a second anti-C5 agent.

In some embodiments, the present methods comprise administering ananti-C5 agent prior to administering two or more PDGF antagonists. Insome embodiments, the present methods comprise administering an anti-C5agent prior to administering a first PDGF antagonist and administeringthe first PDGF antagonist prior to administering a second PDGFantagonist.

In some embodiments, the present methods comprise concurrentlyadministering an anti-C5 agent and Antagonist A or anotherpharmaceutically acceptable salt thereof. In some embodiments, thepresent methods comprise concurrently administering an anti-C5 agent anda first PDGF antagonist prior to administering a second PDGF antagonist.

In some embodiments, the present methods comprise administering ananti-C5 agent prior to concurrently administering a first PDGFantagonist and a second PDGF antagonist.

In some embodiments, the present methods comprise concurrentlyadministering an anti-C5 agent, a first PDGF antagonist and a secondPDGF antagonist.

In some embodiments, the present methods comprise administering a VEGFantagonist prior to administering two or more anti-C5 agents. In someembodiments, the present methods comprise administering a VEGFantagonist prior to administering a first anti-C5 agent andadministering the first anti-C5 agent prior to administering a secondanti-C5 agent.

In some embodiments, the present methods comprise concurrentlyadministering a VEGF antagonist and an anti-C5 agent. In someembodiments, the present methods comprise concurrently administering aVEGF antagonist and a first anti-C5 agent prior to administering asecond anti-C5 agent.

In some embodiments, the present methods comprise administering a VEGFantagonist prior to concurrently administering a first anti-C5 agent anda second anti-C5 agent.

In some embodiments, the present methods comprise concurrentlyadministering a VEGF antagonist, a first anti-C5 agent and a secondanti-C5 agent.

In some embodiments, the present methods comprise administering ananti-C5 agent prior to administering two or more VEGF antagonists. Insome embodiments, the present methods comprise administering an anti-C5agent prior to administering a first VEGF antagonist and administeringthe first VEGF antagonist prior to administering a second VEGFantagonist.

In some embodiments, the present methods comprise concurrentlyadministering an anti-C5 agent and a VEGF antagonist. In someembodiments, the present methods comprise concurrently administering ananti-C5 agent and a first VEGF antagonist prior to administering asecond VEGF antagonist.

In some embodiments, the present methods comprise administering ananti-C5 agent prior to concurrently administering a first VEGFantagonist and a second VEGF antagonist.

In some embodiments, the present methods comprise concurrentlyadministering an anti-C5 agent, a first VEGF antagonist and a secondVEGF antagonist.

In some embodiments, the first agent and second agent are PDGFantagonists, which can be the same or different. In some embodiment, thefirst agent and second agent are VEGF antagonists, which can be the sameor different. In some embodiments, the first agent and second agent areanti-C5 agents, which can be the same or different.

In some embodiments, the first agent and third agent are PDGFantagonists, which can be the same or different. In some embodiment, thefirst agent and third agent are VEGF antagonists, which can be the sameor different. In some embodiments, the first agent and third agent areanti-C5 agents, which can be the same or different.

In some embodiments, the second agent and third agent are PDGFantagonists, which can be the same or different. In some embodiment, thesecond agent and third agent are VEGF antagonists, which can be the sameor different. In some embodiments, the second agent and third agent areanti-C5 agents, which can be the same or different.

Illustrative groups of first agent, second agent and third agent are setforth below in Tables 7, 8, 9 and 10.

TABLE 7 Group First Agent Second Agent Third Agent A PDGF AntagonistVEGF antagonist VEGF antagonist B VEGF antagonist PDGF Antagonist VEGFantagonist C VEGF antagonist VEGF antagonist PDGF Antagonist D PDGFAntagonist Anti-C5 Agent Anti-C5 Agent E Anti-C5 Agent PDGF AntagonistAnti-C5 Agent F Anti-C5 Agent Anti-C5 Agent PDGF Antagonist G PDGFAntagonist PDGF Antagonist VEGF antagonist H PDGF Antagonist VEGFantagonist PDGF Antagonist I VEGF antagonist PDGF Antagonist PDGFAntagonist J PDGF Antagonist PDGF Antagonist Anti-C5 Agent K PDGFAntagonist Anti-C5 Agent PDGF Antagonist L Anti-C5 Agent PDGF AntagonistPDGF Antagonist

TABLE 8 Group First Agent Second Agent Third Agent A PDGF First VEGFSecond VEGF Antagonist antagonist antagonist B First VEGF PDGF SecondVEGF antagonist Antagonist antagonist C First VEGF Second VEGF PDGFantagonist antagonist Antagonist D PDGF First Anti-C5 Second Anti-C5Antagonist Agent Agent E First Anti-C5 PDGF Second Anti-C5 AgentAntagonist Agent F First Anti-C5 Second Anti-C5 PDGF Agent AgentAntagonist G First PDGF Second PDGF VEGF Antagonist Antagonistantagonist H First PDGF VEGF Second PDGF Antagonist antagonistAntagonist I VEGF First PDGF Second PDGF antagonist AntagonistAntagonist J First PDGF Second PDGF Anti-C5 Antagonist Antagonist AgentK First PDGF Anti-C5 Second PDGF Antagonist Agent Antagonist L Anti-C5First PDGF Second PDGF Agent Antagonist Antagonist

TABLE 9 Group First Agent Second Agent Third Agent A Antagonist Aranibizumab Antagonist A B Antagonist A ranibizumab ranibizumab CAntagonist A bevacizumab Antagonist A D Antagonist A bevacizumabbevacizumab E Antagonist A aflibercept Antagonist A F Antagonist Aaflibercept aflibercept G Antagonist A pegaptanib sodium Antagonist A HAntagonist A pegaptanib sodium pegaptanib sodium I Antagonist A ESBA1008Antagonist A J Antagonist A ESBA1008 ESBA1008 K Antagonist A ARC1905Antagonist A L Antagonist A ARC1905 ARC1905 M ranibizumab Antagonist Aranibizumab N ranibizumab Antagonist A Antagonist A O bevacizumabAntagonist A bevacizumab P bevacizumab Antagonist A Antagonist A Qaflibercept Antagonist A aflibercept R aflibercept Antagonist AAntagonist A S pegaptanib sodium Antagonist A pegaptanib sodium Tpegaptanib sodium Antagonist A Antagonist A U ESBA1008 Antagonist AESBA1008 V ESBA1008 Antagonist A Antagonist A W ARC1905 Antagonist AARC1905 X ARC1905 Antagonist A Antagonist A Y ranibizumab ranibizumabAntagonist A Z bevacizumab bevacizumab Antagonist A AA afliberceptaflibercept Antagonist A AB pegaptanib sodium pegaptanib sodiumAntagonist A AC ESBA1008 ESBA1008 Antagonist A AD ARC1905 ARC1905Antagonist A AE ranibizumab ranibizumab bevacizumab AF ranibizumabbevacizumab ranibizumab AG ranibizumab ranibizumab aflibercept AHranibizumab aflibercept ranibizumab AI ranibizumab ranibizumabpegaptanib sodium AJ ranibizumab pegaptanib sodium ranibizumab AKranibizumab ranibizumab ESBA1008 AL ranibizumab ESBA1008 ranibizumab AMranibizumab ranibizumab ARC1905 AN ranibizumab ARC1905 ranibizumab AObevacizumab bevacizumab ranibizumab AP bevacizumab ranibizumabbevacizumab AQ bevacizumab bevacizumab aflibercept AR bevacizumabaflibercept bevacizumab AS bevacizumab bevacizumab pegaptanib sodium ATbevacizumab pegaptanib sodium bevacizumab AU bevacizumab bevacizumabESBA1008 AV bevacizumab ESBA1008 bevacizumab AW bevacizumab bevacizumabARC1905 AX bevacizumab ARC1905 bevacizumab AY aflibercept afliberceptranibizumab AZ aflibercept ranibizumab aflibercept BA afliberceptaflibercept bevacizumab BB aflibercept bevacizumab aflibercept BCaflibercept aflibercept pegaptanib sodium BD aflibercept pegaptanibsodium aflibercept BE aflibercept aflibercept ESBA1008 BF afliberceptESBA1008 aflibercept BG aflibercept aflibercept ARC1905 BH afliberceptARC1905 aflibercept BI pegaptanib sodium pegaptanib sodium ranibizumabBJ pegaptanib sodium ranibizumab pegaptanib sodium BK pegaptanib sodiumpegaptanib sodium bevacizumab BL pegaptanib sodium bevacizumabpegaptanib sodium BM pegaptanib sodium pegaptanib sodium aflibercept BNpegaptanib sodium aflibercept pegaptanib sodium BO pegaptanib sodiumpegaptanib sodium ESBA1008 BP pegaptanib sodium ESBA1008 pegaptanibsodium BQ pegaptanib sodium pegaptanib sodium ARC1905 BR pegaptanibsodium ARC1905 pegaptanib sodium BS ESBA1008 ESBA1008 ranibizumab BTESBA1008 ranibizumab ESBA1008 BU ESBA1008 ESBA1008 bevacizumab BVESBA1008 bevacizumab ESBA1008 BW ESBA1008 ESBA1008 aflibercept BXESBA1008 aflibercept ESBA1008 BY ESBA1008 ESBA1008 pegaptanib sodium BZESBA1008 pegaptanib sodium ESBA1008 CA ESBA1008 ESBA1008 ARC1905 CBESBA1008 ARC1905 ESBA1008 CC ARC1905 ARC1905 ranibizumab CD ARC1905ranibizumab ARC1905 CE ARC1905 ARC1905 bevacizumab CF ARC1905bevacizumab ARC1905 CO ARC1905 ARC1905 aflibercept CH ARC1905aflibercept ARC1905 CI ARC1905 ARC1905 pegaptanib sodium CJ ARC1905pegaptanib sodium ARC1905 CK ARC1905 ARC1905 ESBA1008 CL ARC1905ESBA1008 ESBA1008

TABLE 10 Group First Agent Second Agent Third Agent A Antagonist Aranibizumab bevacizumab B Antagonist A ranibizumab aflibercept CAntagonist A ranibizumab pegaptanib sodium D Antagonist A bevacizumabaflibercept E Antagonist A bevacizumab pegaptanib sodium F Antagonist Aaflibercept pegaptanib sodium G ranibizumab bevacizumab Antagonist A Hranibizumab aflibercept Antagonist A I ranibizumab pegaptanib sodiumAntagonist A J bevacizumab aflibercept Antagonist A K bevacizumabpegaptanib sodium Antagonist A L aflibercept pegaptanib sodiumAntagonist A M ranibizumab Antagonist A bevacizumab N ranibizumabAntagonist A aflibercept O ranibizumab Antagonist A pegaptanib sodium Pbevacizumab Antagonist A aflibercept Q bevacizumab Antagonist Apegaptanib sodium R aflibercept Antagonist A pegaptanib sodium Sbevacizumab ranibizumab Antagonist A T aflibercept ranibizumabAntagonist A U pegaptanib sodium ranibizumab Antagonist A V afliberceptbevacizumab Antagonist A W pegaptanib sodium bevacizumab Antagonist A Xpegaptanib sodium aflibercept Antagonist A Y bevacizumab Antagonist Aranibizumab Z aflibercept Antagonist A ranibizumab AA pegaptanib sodiumAntagonist A ranibizumab AB aflibercept Antagonist A bevacizumab ACpegaptanib sodium Antagonist A bevacizumab AD pegaptanib sodiumAntagonist A aflibercept AE Antagonist A ARC187 ARC1905 AF Antagonist AARC1905 ARC187 AG ARC187 ARC1905 Antagonist A AH ARC1905 ARC187Antagonist A AI ARC187 Antagonist A ARC1905 AJ ARC1905 Antagonist AARC187

In one embodiment, two or more agents are administered concurrently. Inone embodiment, the two or more agents administered concurrently arepresent in the same composition. In another embodiment, the two or moreagents administered concurrently are each present in a separatecomposition.

In certain embodiments, the time period from administration of a firstagent to administration of a second agent is at least 1 min, at least 5min, at least 10 min, at least 15 min, at least 30 min, or at least onehour. In certain embodiments, the time period from administration of afirst agent to administration of a second agent is between 1 min and 2hours, between 5 min and 2 hours, between 10 min and 2 hours, between 15min and 2 hours, between 30 min and 2 hours, between 45 min and 2 hours,between 1 hour and 2 hours, or between 30 min and 1 hour. In certainembodiments, the time period from administration of a first agent toadministration of a second agent is about 1 min, about 2 min, about 3min, about 5 min, about 10 min, about 15 min, about 20 min, about 25min, about 30 min, about 35 min, about 40 min, about 45 min, about 50min, about 55 min, about 60 min, about 90 min, or about 120 min. Incertain embodiments, a second agent is administered within 90 days, 30days, 10 days, 5 days, 2 days, 1 day, 24 hours, 1 hour, 30 minutes, 10minutes, 5 minutes or one minute after administration of a second agent.

In certain embodiments, the time period from administration of a secondagent to administration of a third agent is at least 1 min, at least 5min, at least 10 min, at least 15 min, at least 30 min, or at least onehour. In certain embodiments, the time period between administration ofa second agent and administration of a third agent is between 1 min and2 hours, between 5 min and 2 hours, between 10 min and 2 hours, between15 min and 2 hours, between 30 min and 2 hours, between 45 min and 2hours, between 1 hour and 2 hours, or between 30 min and 1 hour. Incertain embodiments, the time period between administration of a secondagent and administration of a third agent is about 1 min, about 2 min,about 3 min, about 5 min, about 10 min, about 15 min, about 20 min,about 25 min, about 30 min, about 35 min, about 40 min, about 45 min,about 50 min, about 55 min, about 60 min, about 90 min, or about 120min. In certain embodiments, a third agent is administered within 90days, 30 days, 10 days, 5 days, 2 days, 1 day, 24 hours, 1 hour, 30minutes, 10 minutes, 5 minutes or one minute after administration of asecond agent.

In certain embodiments, the time period between concurrentadministration of a first agent and a second agent and administration ofa third agent is at least 1 min, at least 5 min, at least 10 min, atleast 15 min, at least 30 min, or at least one hour. In certainembodiments, the time period between concurrent administration of afirst agent and a second agent and administration of a third agent isbetween 1 min and 2 hours, between 5 min and 2 hours, between 10 min and2 hours, between 15 min and 2 hours, between 30 min and 2 hours, between45 min and 2 hours, between 1 hour and 2 hours, or between 30 min and 1hour. In certain embodiments, the time period from concurrentadministration of a first agent and a second agent to administration ofa third agent is about 1 min, about 2 min, about 3 min, about 5 min,about 10 min, about 15 min, about 20 min, about 25 min, about 30 min,about 35 min, about 40 min, about 45 min, about 50 min, about 55 min,about 60 min, about 90 min, or about 120 min. In certain embodiments,administration of a third agent is within 90 days, 30 days, 10 days, 5days, 2 days, 1 day, 24 hours, 1 hour, 30 minutes, 10 minutes, 5 minutesor one minute of concurrent administration of a first agent and a secondagent.

In certain embodiments, the time period from administration of a firstagent to concurrent administration a second agent and a third agent isat least 1 min, at least 5 min, at least 10 min, at least 15 min, atleast 30 min, or at least one hour. In certain embodiments, the timeperiod from administration of a first agent to concurrent administrationof a second agent and a third agent is between 1 min and 2 hours,between 5 min and 2 hours, between 10 min and 2 hours, between 15 minand 2 hours, between 30 min and 2 hours, between 45 min and 2 hours,between 1 hour and 2 hours, or between 30 min and 1 hour. In certainembodiments, the time period from administration of a first agent toconcurrent administration of a second agent and a third agent is about 1min, about 2 min, about 3 min, about 5 min, about 10 min, about 15 min,about 20 min, about 25 min, about 30 min, about 35 min, about 40 min,about 45 min, about 50 min, about 55 min, about 60 min, about 90 min, orabout 120 min. In certain embodiments, concurrent administration of asecond agent and a third agent is within 90 days, 30 days, 10 days, 5days, 2 days, 1 day, 24 hours, 1 hour, 30 minutes, 10 minutes, 5 minutesor one minute of administration of a first agent.

The administration of two or more, such as three or more, active agents(e.g., Antagonist A or another pharmaceutically acceptable salt thereof,a VEGF antagonist and an anti-C5 agent) can have a synergistic effect intreating or preventing a disease or disorder, e.g., an ophthalmologicaldisease or disorder. For example, administration of Antagonist A oranother pharmaceutically acceptable salt thereof, VEGF antagonist andanti-C5 agent (or any two of these active agents) can improve retinalattachment success, improve visual acuity, reduce choroidalneovascularization or stabilize vision to a degree that is greater thanan additive effect of the active agents.

In certain embodiments, the invention provides methods for treating orpreventing an ophthalmological disease or disorder, comprisingadministering to a subject in need thereof one or more, in someembodiments two or more or three or more, active agents via anapparatus. In other embodiments, the methods further comprise performingsurgery on the subject. In other embodiments, the methods furthercomprise administering another active agent, such as an antineoplasticdrug, including but not limited to any of those described herein. Inparticular embodiments, the methods further comprise administeringanother active agent and performing surgery on the subject.

In some embodiments, administration of Antagonist A or anotherpharmaceutically acceptable salt thereof, and optionally a VEGFantagonist and/or an anti-C5 agent to a subject results in improvedvision, such as increased visual acuity. In some embodiments, thesubject experienced moderate vision loss, defined as losing 15 lettersor more from baseline on ETDRS visual acuity testing, measured at week24, prior to treatment with Antagonist A or another pharmaceuticallyacceptable salt thereof.

In some embodiments, visual acuity testing is as described in EarlyTreatment Diabetic Retinopathy Study Research Group (ETDRS), Manual ofOperations, Baltimore: ETDRS Coordinating Center, University ofMaryland. Available from: National Technical Information Service, 5285Port Royal Road, Springfield, Va. 22161; Accession No. PB85 223006/AS;Ferris et al., Am J Ophthalmol 94:91-96, 1982; or or Example 4, asdescribed herein. In some embodiments, the visual acuity testing usesone or more charts available fromhttp://www.nei.nih.gov/photo/keyword.asp?conditions=Eye+Charts&match=all,e.g., ETDRS visual acuity Chart 1, 2 and/or R.

In other embodiments, administration of Antagonist A or anotherpharmaceutically acceptable salt thereof and a VEGF antagonist resultsin fewer ocular adverse events, a decrease in size of RCH (e.g.,measured by fundus photography and FA), a decrease in exudation(measured by fundus photography, OCT, and FA), or a decrease inepiretinal proliferation or retinal traction (assessed by fundusphotography), compared to those experienced by a subject who was notadministered with Antagonist A or another pharmaceutically acceptablesalt thereof. In some embodiments, the subject does not require, and themethods do not comprise, ablative treatment of RCH or ocular surgery.

In some embodiments, administration of Antagonist A or anotherpharmaceutically acceptable salt thereof, and optionally a VEGFantagonist and/or an anti-C5 agent, to a subject results in improvedvision independent of baseline lesion size or baseline vision, comparedto vision of a subject who was not administered with Antagonist A oranother pharmaceutically acceptable salt thereof, or compared to asubject administered anti-VEGF monotherapy. In some embodiments,administration of Antagonist A or another pharmaceutically acceptablesalt thereof, and optionally a VEGF antagonist and/or an anti-C5 agent,to a subject results in the subject having a visual acuity of 20/40 orbetter, or 20/25 or better vision. In some embodiments, administrationof Antagonist A or another pharmaceutically acceptable salt thereof, andoptionally a VEGF antagonist and/or an anti-C5 agent to a subjectresults in an increased reduction in CNV size in the subject, comparedto CNV size in a patient who was not administered with Antagonist A oranother pharmaceutically acceptable salt thereof, or compared to asubject administered anti-VEGF monotherapy. In some embodiments,administration of Antagonist A or another pharmaceutically acceptablesalt thereof, and optionally a VEGF antagonist and/or an anti-C5 agent,to a subject results in a reduction in CNV size (e.g., reduction in discarea (DA) size). In some embodiments, administration of Antagonist A oranother pharmaceutically acceptable salt thereof, and optionally a VEGFantagonist and/or an anti-C5 agent to a subject result in an increasedreduction in DA in the subject, compared to DA in a patient who was notadministered with Antagonist A or another pharmaceutically acceptablesalt thereof, or compared to a subject administered anti-VEGFmonotherapy. In some embodiments, the increased reduction in CNV size isin subjects with small baseline CNV, e.g., less than or equal to 1.62 DA(disc area). In some embodiments, the increased reduction in CNV size(e.g., in disc area) is in subjects with large baseline CNV, e.g.,greater than 1.62 DA. In some embodiments, administration of AntagonistA or another pharmaceutically acceptable salt thereof, and optionally aVEGF antagonist and/or an anti-C5 agent, to a subject results inneovascular regression. In some embodiments, administration ofAntagonist A or another pharmaceutically acceptable salt thereof, andoptionally a VEGF antagonist and/or an anti-C5 agent, to a subjectresults in reduced neovascular growth, compared to that occurring in asubject who was not administered with Antagonist A or anotherpharmaceutically acceptable salt thereof, or compared to a subjectadministered anti-VEGF monotherapy. In some embodiments, the reducedneovascular growth is anti-fibrosis. In some embodiments, administrationof Antagonist A or another pharmaceutically acceptable salt thereof, andoptionally a VEGF antagonist and/or an anti-C5 agent, to a subjectresults in a decrease in or absence of hyper-reflective material, e.g.,sub-retinal hyper-reflective material, such as a decrease in the size ofsub-retinal hyper-reflective material (SHRM) as evidenced by spectraldomain optical coherence tomography (SD-OCT). In some embodiments,administration of Antagonist A or another pharmaceutically acceptablesalt thereof, and optionally a VEGF antagonist and/or an anti-C5 agent,to a subject results in an increase in resolution of hyper-reflectivematerial, e.g., sub-retinal hyper-reflective material, such as comparedto a subject who was not administered with Antagonist A or anotherpharmaceutically acceptable salt thereof, or compared to a subjectadministered a VEGF antagonist, anti-VEGF monotherapy, and/or an anti-C5agent.

In some embodiments, a subject with improved vision has a greater than3-line, 4-line or 5-line gain in visual acuity. In one embodiment, asubject's visual acuity is determined using a protocol such as the EarlyTreatment for Diabetic Retinopathy Study (“ETDRS”) or the Age-RelatedEye Disease Study (“AREDS”) protocol. In some embodiments, visual acuityis measured using a modified ETDRS and/or AREDS protocol, such as themeasurement of visual acuity described in Ferris et al., Am J Ophthalmol94:91-96, 1982. In some embodiments, visual acuity is measured asdescribed in Early Treatment Diabetic Retinopathy Study Research Group(ETDRS), Manual of Operations, Baltimore: ETDRS Coordinating Center,University of Maryland. Available from: National Technical InformationService, 5285 Port Royal Road, Springfield, Va. 22161; Accession No.PB85 223006/AS. In other embodiments, visual acuity testing is measuredas described in Example 4 below. In some embodiments, the visual acuitytesting uses one or more charts available fromhttp://www.nei.nih.gov/photo/keyword.asp?conditions=Eye+Charts&match=all,e.g., ETDRS visual acuity Chart 1, 2 and/or R.

In one embodiment, a subject's visual acuity is determined by one ormore of the following procedures: (1) measurement of best-correctedvisual acuity (BCVA) with required manifest refraction; (2) measurementof corrected visual acuity with conditional manifest refraction; or (3)measurement of corrected visual acuity without manifest refraction.

In one embodiment, each of the PDGF and VEGF antagonists is administeredin an amount effective to treat or prevent an ophthalmological diseaseor disorder. The amount of antagonist that is admixed with the carriermaterials to produce a single dosage can vary depending upon the subjectbeing treated and the particular mode of administration.

The dosage of each antagonist can depend on several factors includingthe severity of the condition, whether the condition is to be treated orprevented, and the age, weight, and health of the person to be treated.Additionally, pharmacogenomic (the effect of genotype on thepharmacokinetic, pharmacodynamic or efficacy profile of a therapeutic)information about a particular patient may affect dosage used.Furthermore, the exact individual dosages can be adjusted somewhatdepending on a variety of factors, including the specific combination ofantagonists being administered, the time of administration, the route ofadministration, the nature of the formulation, the rate of excretion,the particular ophthalmological disease or disorder being treated, theseverity of the disorder, and the anatomical location of the neovasculardisorder. Some variations in the dosage can be expected.

Generally, when orally administered to a subject, the dosage of anantagonist of the present invention is normally 0.001 mg/kg/day to 100mg/kg/day, 0.01 mg/kg/day to 50 mg/kg/day, or 0.1 mg/kg/day to 10mg/kg/day. Generally, when orally administered to a human, the dosage ofan antagonist of the present invention is normally 0.001 mg to 300 mgper day, 1 mg to 200 mg per day, or 5 mg to 50 mg per day. Dosages up to200 mg per day may be necessary. For administration of an antagonist ofthe present invention by parenteral injection, the dosage is normally0.1 mg to 250 mg per day, 1 mg to 20 mg per day, or 3 mg to 5 mg perday. Injections may be given up to four times daily. In someembodiments, the dosage of a PDGF or VEGF antagonist for use in thepresent invention is normally 0.1 mg to 1500 mg per day, or 0.5 mg to 10mg per day, or 0.5 mg to 5 mg per day. A dosage of up to 3000 mg per daycan be administered.

In some embodiments, for administration by parenteral injection of athree active agents (e.g., Antagonist A or another pharmaceuticallyacceptable salt thereof, VEGF antagonist and an anti-C5 agent or othercombination disclosed herein), the dosage of each of the PDGFantagonist, VEGF antagonist and anti-C5 agent, is typically 0.1 mg to250 mg per day, 1 mg to 20 mg per day, or 3 mg to 5 mg per day.Injections may be given up to four times daily. Generally, whenparenterally administered, the dosage of Antagonist A or anotherpharmaceutically acceptable salt thereof, VEGF antagonist, or anti-C5agent is typically 0.1 mg to 1500 mg per day, or 0.5 mg to 10 mg perday, or 0.5 mg to 5 mg per day. A dosage of at least up to 3000 mg perday can be administered.

In some embodiments, in which Antagonist A or another pharmaceuticallyacceptable salt thereof, VEGF antagonist and/or anti-C5 agent areophthalmologically administered to a human, for example intravitreally,the dosage of each of Antagonist A or another pharmaceuticallyacceptable salt thereof, VEGF antagonist and anti-C5 agent is typically0.003 mg to 5.0 mg per eye per administration, or 0.03 mg to 3.0 mg pereye per administration, or 0.1 mg to 1.0 mg per eye per administration.In one embodiment, the dosage of each of Antagonist A or anotherpharmaceutically acceptable salt thereof, VEGF antagonist and anti-C5agent is about 0.03 mg, about 0.3 mg, about 0.5 mg, about 1.0 mg, about1.25 mg, about 1.5 mg, about 2.0 mg or about 3.0 mg per eye. In oneembodiment, the dosage Antagonist A or another pharmaceuticallyacceptable salt thereof is about 0.03 mg, about 0.3 mg, about 0.5 mg,about 1.0 mg, about 1.25 mg, about 1.5 mg, about 2.0 mg, about 3.0 mg,or about 4.0 mg per eye. In another embodiment, the dosage of a VEGFantagonist (e.g., ranibizumab, bevacizumab, aflibercept, ESBA1008 orpegaptanib sodium) is about 0.03 mg, about 0.3 mg, about 0.5 mg, about1.0 mg, about 1.25 mg, about 1.5 mg, about 1.65 mg, about 2.0 mg, about3.0 mg, or about 4.0 mg per eye. In another embodiment, the dosage ofthe anti-C5 agent (e.g., ARC1905 or a pharmaceutically acceptable saltthereof) is about 0.03 mg, about 0.3 mg, about 0.5 mg, about 1.0 mg,about 1.25 mg, about 1.5 mg, about 1.65 mg, about 2.0 mg, about 3.0 mg,or about 4.0 per eye.

In certain embodiments where a subject is administered both Antagonist Aor another pharmaceutically acceptable salt thereof and a VEGFantagonist, and optionally an anti-C5 agent, the dosage of Antagonist Aor another pharmaceutically acceptable salt thereof) is about 1.5 mg,and the dosage of the VEGF antagonist (e.g., ranibizumab) is about 0.5mg. In certain embodiments where a subject is administered bothAntagonist A or another pharmaceutically acceptable salt thereof and aVEGF antagonist, the dosage of Antagonist A or another pharmaceuticallyacceptable salt thereof is about 3.0 mg, and the dosage of the VEGFantagonist (e.g., ranibizumab) is about 0.5 mg. In certain embodiments,a subject is administered both Antagonist A or another pharmaceuticallyacceptable salt thereof and a VEGF antagonist, wherein the dosage ofAntagonist A or another pharmaceutically acceptable salt thereof) isabout 1.5 mg, and the dosage of the VEGF antagonist (e.g., bevacizumab)is about 1.25 mg. In certain embodiments, a subject is administered bothAntagonist A or another pharmaceutically acceptable salt thereof and aVEGF antagonist, wherein the dosage of Antagonist A or anotherpharmaceutically acceptable salt thereof is about 3.0 mg, and the dosageof the VEGF antagonist (e.g., bevacizumab) is about 1.25 mg. In certainembodiments, a subject is administered both Antagonist A or anotherpharmaceutically acceptable salt thereof and a VEGF antagonist, whereinthe dosage of Antagonist A or another pharmaceutically acceptable saltthereof is about 1.5 mg, and the dosage of the VEGF antagonist (e.g.,aflibercept) is about 2.0 mg. In certain embodiments, a subject isadministered both Antagonist A or another pharmaceutically acceptablesalt thereof and a VEGF antagonist, wherein the dosage of Antagonist Aor another pharmaceutically acceptable salt thereof is about 3.0 mg, andthe dosage of the VEGF antagonist (e.g., aflibercept) is about 2.0 mg.In certain embodiments, a subject is administered both Antagonist A oranother pharmaceutically acceptable salt thereof and a VEGF antagonist,wherein the dosage of Antagonist A or another pharmaceuticallyacceptable salt thereof is about 1.5 mg, and the dosage of the VEGFantagonist, e.g., pegaptanib sodium, is about 1.65 mg. In certainembodiments, a subject is administered both Antagonist A or anotherpharmaceutically acceptable salt thereof and a VEGF antagonist, whereinthe dosage of Antagonist A or another pharmaceutically acceptable saltthereof is about 3.0 mg, and the dosage of the VEGF antagonist, e.g.,pegaptanib sodium, is about 1.65 mg.

The dosage can range from about 0.01 mL to about 0.2 mL administered pereye, or about 0.03 mL to about 0.15 mL administered per eye, or about0.05 mL to about 0.10 mL administered per eye.

Antagonist A or a pharmaceutically acceptable salt thereof can bedelivered intravitreally at up to about 30 mg/ml with injection volumesup to 100 μL.

Illustrative Antagonist A/VEGF antagonist combination pairs and theirdosages are set forth in Table 11:

TABLE 11 Combin- ation No. PDGF Antagonist VEGF Antagonist 1 AntagonistA ranibizumab (about 1.5 mg) (about 0.5 mg) 2 Antagonist A ranibizumab(about 3.0 mg) (about 0.5 mg) 3 Antagonist A bevacizumab (about 1.5 mg)(about 1.25 mg) 4 Antagonist A bevacizumab (about 3.0 mg) (about 1.25mg) 5 Antagonist A aflibercept (about 1.5 mg) (about 2.0 mg) 6Antagonist A aflibercept (about 3.0 mg) (about 2.0 mg) 7 Antagonist Apegaptanib sodium (about 3.0 mg) (about 1.65 mg) 8 Antagonist Apegaptanib sodium (about 3.0 mg) (about 1.65 mg)

In particular embodiments wherein the subject is administered an anti-C5agent in combination with Antagonist A or another pharmaceuticallyacceptable salt thereof and the VEGF antagonist, the anti-C5 agent maybe administered at a dosage of about 0.03 mg, about 0.3 mg, about 0.5mg, about 1.0 mg, about 1.25 mg, about 1.5 mg, about 2.0 mg or about 3.0mg per eye.

In certain embodiments, ocular dosages of compositions comprisinganti-C5 aptamers, such as ARC1905 and ARC187, or a pharmaceuticallyacceptable salt thereof, can range from about 0.01 mg to about 5 mg/eyeor from about 0.1 mg to about 3 mg/eye. For instance, ocular dosages ofcompositions comprising ARC1905, ARC187, or a pharmaceuticallyacceptable salt thereof may be about 0.01 mg, about 0.03 mg, about 0.05mg, about 0.1 mg, about 0.3 mg, about 0.5 mg, about 1 mg, about 1.5 mg,about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about4.5 mg, or about 5 mg. Such dosages may be administered ocularly, forexample by intravitreal injection, weekly, biweekly, monthly, orquarterly, optionally by a sustained release device or formulation. Insome embodiments, the anti-C5 aptamers (e.g., ARC1905, ARC187, or apharmaceutically acceptable salt thereof) can be administered inmultiple injections (e.g., intravitreal injections) over a period ofmonths separated by varying time intervals. In certain such embodiments,initial injections received early in the treatment regimen are separatedby a shorter interval than injections received later in the treatmentregimen. For instance, one dosage regimen, particularly useful inmethods for treating, preventing, or stabilizing AMD (e.g.,non-exudative type AMD or geographic atrophy), comprises administeringinitial injections at the start of treatment (e.g., first two, three,four, or five injections) of anti-C5 aptamer (e.g., ARC1905, ARC187, ora pharmaceutically acceptable salt thereof) on a monthly basis andadministering subsequent injections at longer intervals (e.g., everythree, four, five, or six months). By way of example, the first threeinjections of anti-C5 aptamer are administered to a subject every month,whereas the fourth and fifth injections are administered three or fourmonths after the previous injection. Intervals between injections ofanti-C5 aptamer may be adjusted based on the subject's response totreatment as measured, for example, by change in geographic atrophylesion size or improvement or stabilization of visual acuity.

In some embodiments, an anti-C5 aptamer is administered to a subjectwith a VEGF antagonist, wherein the dosage of the anti-C5 aptamer isabout 0.03 mg, and the dosage of the VEGF antagonist, e.g., ranibizumab,is about 0.5 mg. In certain embodiments, a subject is administered bothan anti-C5 aptamer and a VEGF antagonist, wherein the dosage of theanti-C5 aptamer is about 1.0 mg, and the dosage of the VEGF antagonist,e.g., ranibizumab, is about 0.5 mg. In certain embodiments, a subject isadministered both an anti-C5 aptamer and a VEGF antagonist, wherein thedosage of the anti-C5 aptamer is about 2.0 mg, and the dosage of theVEGF antagonist, e.g., ranibizumab, is about 0.5 mg.

In some embodiments, an anti-C5 aptamer is administered to a subjectwith a VEGF antagonist, wherein the dosage of the anti-C5 aptamer isabout 0.03 mg, and the dosage of the VEGF antagonist, e.g., bevacizumab,is about 1.25 mg. In certain embodiments, a subject is administered bothan anti-C5 aptamer and a VEGF antagonist, wherein the dosage of theanti-C5 aptamer is about 1.0 mg, and the dosage of the VEGF antagonist,e.g., bevacizumab, is about 1.25 mg. In certain embodiments, a subjectis administered both an anti-C5 aptamer and a VEGF antagonist, whereinthe dosage of the anti-C5 aptamer is about 2.0 mg, and the dosage of theVEGF antagonist, e.g., bevacizumab, is about 1.25 mg.

In some embodiments, an anti-C5 aptamer is administered to a subjectwith a VEGF antagonist, wherein the dosage of the anti-C5 aptamer isabout 0.03 mg, and the dosage of the VEGF antagonist, e.g., aflibercept,is about 2.0 mg. In certain embodiments, a subject is administered bothan anti-C5 aptamer and a VEGF antagonist, wherein the dosage of theanti-C5 aptamer is about 1.0 mg, and the dosage of the VEGF antagonist,e.g., aflibercept, is about 2.0 mg. In certain embodiments, a subject isadministered both an anti-C5 aptamer and a VEGF antagonist, wherein thedosage of the anti-C5 aptamer is about 2.0 mg, and the dosage of theVEGF antagonist, e.g., aflibercept, is about 2.0 mg.

Administration of each antagonist can, independently, be one to fourtimes daily or one to four times per month or one to six times per yearor once every two, three, four or five years. Administration can be forthe duration of one day or one month, two months, three months, sixmonths, one year, two years, three years, and may even be for the lifeof the patient. In one embodiment, the administration is performed oncea month for three months. Chronic, long-term administration will beindicated in many cases. The dosage may be administered as a single doseor divided into multiple doses. In general, the desired dosage should beadministered at set intervals for a prolonged period, usually at leastover several weeks or months, although longer periods of administrationof several months or years or more may be needed.

In addition to treating pre-existing ophthalmological diseases anddisorders, the compositions can be administered prophylactically inorder to prevent or slow the onset of these disease and disorders. Theterm “prevent” encompasses inhibiting or delaying the onset orprogression of a disease or disorder. In prophylactic applications, thecomposition can be administered to a patient susceptible to or otherwiseat risk of a particular ophthalmological disease or disorder.

In one embodiment, Antagonist A or another pharmaceutically acceptablesalt thereof and the VEGF antagonist are administered to a subject inneed of treatment therewith, typically in the form of an injectablepharmaceutical composition. Antagonist A or another pharmaceuticallyacceptable salt thereof and VEGF antagonist can be administered eitherin separate compositions or in a pharmaceutical composition comprisingboth the PDGF antagonist and VEGF antagonist. The administration can beby injection, for example by intraocular injection, or by using a drugdelivery device. Parenteral, systemic, or transdermal administration isalso within the scope of the invention. The administration of AntagonistA or another pharmaceutically acceptable salt thereof and the VEGFantagonist can be sequential in time or concurrent. When administeredsequentially, the administration of each can be by the same or differentroute. In one embodiment, Antagonist A or another pharmaceuticallyacceptable salt thereof is administered within 90 days, 30 days, 10days, 5 days, 24 hours, 1 hour, 30 minutes, 10 minutes, 5 minutes or oneminute of administration of a VEGF antagonist. Where Antagonist A oranother pharmaceutically acceptable salt thereof is administered priorto the VEGF antagonist, the VEGF antagonist is administered within atime and in an amount such that the total amount of Antagonist A oranother pharmaceutically acceptable salt thereof and VEGF antagonist iseffective to treat or prevent an ophthalmological disease or disorder.Where the VEGF antagonist is administered prior to Antagonist A oranother pharmaceutically acceptable salt thereof, Antagonist A oranother pharmaceutically acceptable salt thereof is administered withina time and in an amount such that the total amount of Antagonist A oranother pharmaceutically acceptable salt thereof and VEGF antagonist iseffective to treat or prevent an ophthalmological disease or disorder.

In one embodiment, Antagonist A or another pharmaceutically acceptablesalt thereof or VEGF antagonist (e.g., ranibizumab, bevacizumab,pegaptanib sodium, ESBA1008 or aflibercept) is administeredintravitreally with a 30-gauge or 27-gauge needle. In some embodiments,a 0.5 inch needle is used. In one embodiment, Antagonist A or anotherpharmaceutically acceptable salt thereof is administered intravitreallywith a 30-gauge 0.5 inch needle and a VEGF antagonist (e.g.,ranibizumab, bevacizumab, pegaptanib sodium, ESBA1008 or aflibercept) isadministered intravitreally with a 27-gauge needle. In some embodiments,50 μL (1.5 mg in 0.05 mL) of Antagonist A or another pharmaceuticallyacceptable salt thereof is administered intravitreally with a 30-gauge0.5 inch needle and 50 μL (0.5 mg in 0.05 mL) of a VEGF antagonist(e.g., ranibizumab, bevacizumab, pegaptanib sodium or aflibercept) isadministered intravitreally with a 27-gauge needle.

In certain embodiments where Antagonist A or another pharmaceuticallyacceptable salt thereof such as Antagonist A or another pharmaceuticallyacceptable salt thereof is used in combination with a VEGF antagonist,such as ranibizumab, bevacizumab, ESBA1008, pegaptanib sodium oraflibercept, one of these two agents is first administered to thesubject, and then the other agent is administered to the subject. Inparticular embodiments, the two agents are both administered to the sameeye of the subject. In particular embodiments, the two agents are bothadministered to both eyes of the subject. The two agents may beadministered to an eye in either order, i.e., Antagonist A or anotherpharmaceutically acceptable salt thereof may be administered first, andthen the VEGF antagonist administered, or the VEGF antagonist may beadministered first, and then Antagonist A or another pharmaceuticallyacceptable salt thereof administered. The agent administered second maybe administered immediately following administration of the agentadministered first, or the agent administered second may be administeredafter a time period following administration of the agent administeredfirst.

In certain embodiments, the time period from administration of the firstagent to administration of the second agent is at least 1 min, at least5 min, at least 10 min, at least 15 min, at least 30 min, or at leastone hour. In certain embodiments, the time period from administration ofthe first agent to administration of the second agent is between 1 minand 2 hours, between 5 min and 2 hours, between 10 min and 2 hours,between 15 min and 2 hours, between 30 min and 2 hours, between 45 minand 2 hours, between 1 hour and 2 hours, or between 30 min and 1 hour.In certain embodiments, the time period from administration of the firstagent to administration of the second agent is about 1 min, about 2 min,about 3 min, about 5 min, about 10 min, about 15 min, about 20 min,about 25 min, about 30 min, about 35 min, about 40 min, about 45 min,about 50 min, about 55 min, about 60 min, about 90 min, or about 120min.

In certain embodiments, the present invention provides methods fortreating or preventing any of the ophthalmological diseases describedherein, comprising providing to a subject in need thereof. Antagonist Aor another pharmaceutically acceptable salt thereof at a first timepoint, and providing to the subject a VEGF antagonist, e.g.,aflibercept, bevacizumab, ranibizumab, ESBA1008, or pegaptanib sodium,at a second time point, wherein the amount of time between the firsttime point and the second time point is about 1 min, about 2 min, about5 min, about 10 min, about 15 min, about 20 min, about 25 min, about 30min, about 40 min, about 50 min, about 60 min, about 90 min, about 2hours, about 4 hours, about 6 hours, about 8 hours, about 12 hours,about 24 hours, about 36 hours, about 48 hours, about three days, aboutfour days, about five days, about six days, or about seven days.

In certain embodiments, Antagonist A or another pharmaceuticallyacceptable salt thereof and the VEGF antagonist are administeredintravitreally. In certain embodiments, about 1.5 mg or 3.0 mg ofAntagonist A or another pharmaceutically acceptable salt thereof to aneye, and about 0.5 mg, about 1.25 mg, about 1.65 mg, or about 2.0 mg ofthe VEGF antagonist is administered to an eye. In some embodiments, theVEGF antagonist is administered intravitreally about 30 minutes afterAntagonist A or another pharmaceutically acceptable salt thereof isadministered intravitreally. In some embodiments, Antagonist A oranother pharmaceutically acceptable salt thereof is administeredintravitreally about 30 minutes after the VEGF antagonist isadministered intravitreally.

In one embodiment, a VEGF antagonist is administered to at least one eyeof the subject, about 1 hour is allowed to elapse followingadministration of the VEGF antagonist, and then Antagonist A or anotherpharmaceutically acceptable salt thereof is administered to the sameeye. In one embodiment, Antagonist A or another pharmaceuticallyacceptable salt thereof is administered to at least one eye of thesubject, about 1 hour is allowed to lapse following administration ofthe PDGF antagonist, and then a VEGF antagonist is administered to thesame eye.

In certain embodiments, the PDGF antagonist and the VEGF antagonist areadministered to each eye in a total combined volume of less than orabout 50 μL, less than or about 60 μL, less than or about 70 μL, lessthan or about 80 μL, less than or about 90 μL, less than or about 100μL, less than or about 120 μL, less than or about 150 μL, or less thanor about 200 μL.

In certain embodiments, Antagonist A or another pharmaceuticallyacceptable salt thereof, VEGF antagonist and anti-C5 agent areadministered intraocularly, e.g., intravitreally. In particularembodiments, Antagonist A or another pharmaceutically acceptable saltthereof, VEGF antagonist and anti-C5 agent are administered to themammal via a single injection, e.g., a single intraocular orintravitreal injection. In particular embodiments, Antagonist A oranother pharmaceutically acceptable salt thereof, VEGF antagonist andanti-C5 agent are administered sequentially. In certain embodiments, twoor more of Antagonist A or another pharmaceutically acceptable saltthereof, a VEGF antagonist and an anti-C5 agent are administered at thesame time, e.g., in the same composition. In particular embodiments, oneof Antagonist A or another pharmaceutically acceptable salt thereof, aVEGF antagonist and an anti-C5 agent is administered, and within about30 seconds, one or two of others are subsequently administered. Inparticular embodiments, all three of Antagonist A or anotherpharmaceutically acceptable salt thereof, a VEGF antagonist and ananti-C5 agent are administered within about 30 seconds or one minute ofeach other. In other embodiments, one of Antagonist A or anotherpharmaceutically acceptable salt thereof, a VEGF antagonist and ananti-C5 agent is administered, and one or both of the others areadministered about 1 min, about 2 min, about 5 min, about 10 min, about15 min, about 20 min, about 25 min, about 30 min, about 40 min, about 50min, about 60 min, about 90 min, about 2 hours, about 4 hours, about 6hours, about 8 hours, about 12 hours, about 24 hours, about 36 hours,about 48 hours, about three days, about four days, about five days,about six days, or about seven days later. In other embodiments, one ortwo of Antagonist A or another pharmaceutically acceptable salt thereof,VEGF antagonist and anti-C5 agent are administered, and the other isadministered about 1 min, about 2 min, about 5 min, about 10 min, about15 min, about 20 min, about 25 min, about 30 min, about 40 min, about 50min, about 60 min, about 90 min, about 2 hours, about 4 hours, about 6hours, about 8 hours, about 12 hours, about 24 hours, about 36 hours,about 48 hours, about three days, about four days, about five days,about six days, or about seven days later. In certain embodiments, oneof the PDGF antagonist, VEGF antagonist and anti-C5 agent isadministered; and another is administered about 1 min, about 2 min,about 5 min, about 10 min, about 15 min, about 20 min, about 25 min,about 30 min, about 40 min, about 50 min, about 60 min, about 90 min,about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 12hours, about 24 hours, about 36 hours, about 48 hours, about three days,about four days, about five days, about six days, or about seven dayslater; and the remaining one is administered about 1 min, about 2 min,about 5 min, about 10 min, about 15 min, about 20 min, about 25 min,about 30 min, about 40 min, about 50 min, about 60 min, about 90 min,about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 12hours, about 24 hours, about 36 hours, about 48 hours, about three days,about four days, about five days, about six days, or about seven dayslater. In certain embodiments wherein two of Antagonist A or anotherpharmaceutically acceptable salt thereof, VEGF antagonist and anti-C5agent are present in the same composition, the composition isadministered and the PDGF antagonist, VEGF antagonist or anti-C5 agentthat is not present in the composition is administered about 1 min,about 2 min, about 5 min, about 10 min, about 15 min, about 20 min,about 25 min, about 30 min, about 40 min, about 50 min, about 60 min,about 90 min, about 2 hours, about 4 hours, about 6 hours, about 8hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours,about three days, about four days, about five days, about six days, orabout seven days later. In other embodiments wherein two of Antagonist Aor another pharmaceutically acceptable salt thereof, VEGF antagonist andanti-C5 agent are present in the same composition, Antagonist A oranother pharmaceutically acceptable salt thereof, VEGF antagonist oranti-C5 agent that is not present in the composition is administered,and the composition is administered about 1 min, about 2 min, about 5min, about 10 min, about 15 min, about 20 min, about 25 min, about 30min, about 40 min, about 50 min, about 60 min, about 90 min, about 2hours, about 4 hours, about 6 hours, about 8 hours, about 12 hours,about 24 hours, about 36 hours, about 48 hours, about three days, aboutfour days, about five days, about six days, or about seven days later.

In certain embodiments, Antagonist A or another pharmaceuticallyacceptable salt thereof, e.g., Antagonist A or another pharmaceuticallyacceptable salt thereof, is administered about every 24 hours for two ormore, three or more, four or more, five or more, six or more, or sevenor more days, and a VEGF antagonist, e.g., aflibercept, bevacizumab,ESBA1008, pegaptanib sodium or ranimizumab, is administered about 48hours following the first administration of Antagonist A or anotherpharmaceutically acceptable salt thereof. In certain embodiments,Antagonist A or another pharmaceutically acceptable salt thereof isadministered on each of four successive days, i.e., day 1, day 2, day 3and day 4, and the VEGF antagonist (e.g., bevacizumab, ranicizumab,ESBA1008, pegaptanib sodium or aflibercept) is administered on the thirdday, i.e., day 3. In particular embodiments, a composition comprisingAntagonist A or another pharmaceutically acceptable salt thereof, e.g.,Antagonist A or another pharmaceutically acceptable salt thereof, isadministered to a subject, and a composition comprising a VEGFantagonist is administered to the subject about forty-eight hours later.

In one embodiment, about 50 mg/kg of Antagonist A or anotherpharmaceutically acceptable salt thereof (e.g., Antagonist A or anotherpharmaceutically acceptable salt thereof) is administered, e.g.,intraperitoneally, on day 1, day 2, day 3 and day 4, and about 1 mg/kgof a VEGF antagonist (e.g., bevacizumab, ranibizumab, ESBA1008,pegaptanib sodium, or aflibercept) is administered on day 3. In oneembodiment, about 50 mg/kg of Antagonist A or another pharmaceuticallyacceptable salt thereof (e.g., Antagonist A or another pharmaceuticallyacceptable salt thereof) is administered on day 1, day 2, day 3 and day4, and about 5 mg/kg of a VEGF antagonist (e.g., bevacizumab,ranibizumab, ESBA1008, pegaptanib sodium, or aflibercept) isadministered on day 3.

In one embodiment, about 50 mg/kg of Antagonist A or anotherpharmaceutically acceptable salt thereof is administered on day 1, day2, day 3 and day 4, and about 1 mg/kg of aflibercept is administered onday 3. In one embodiment, about 50 mg/kg of Antagonist A or anotherpharmaceutically acceptable salt thereof is administered on day 1, day2, day 3 and day 4, and about 5 mg/kg of aflibercept is administered onday 3.

In one embodiment, about 0.03 mg, about 0.3 mg, about 0.5 mg, about 1.0mg, about 1.5 mg or about 3.0 mg of Antagonist A or anotherpharmaceutically acceptable salt thereof (e.g., Antagonist A or anotherpharmaceutically acceptable salt thereof) is administered intravitreallyon day 1, day 2, day 3 and day 4, and about 0.5 mg, about 1.0 mg, about1.5 mg, about 1.65 mg, about 3.0 mg, or about 4.0 mg of a VEGFantagonist (e.g., bevacizumab, ranibizumab, ESBA1008, pegaptanib sodium,or aflibercept) is administered intravitreally on day 3. In oneembodiment, about 0.3 mg or about 1.5 mg of Antagonist A or anotherpharmaceutically acceptable salt thereof is administered intravitreallyon day 1, day 2, day 3 and day 4, and about 0.5 mg of ranibizumab isadministered intravitreally on day 3. In one embodiment, about 0.3 mg orabout 1.5 mg of Antagonist A or another pharmaceutically acceptable saltthereof is administered intravitreally on day 1, day 2, day 3 and day 4,and about 1.25 mg of bevacizumab is administered intravitreally on day3. In one embodiment, about 0.3 mg or about 1.5 mg of Antagonist A oranother pharmaceutically acceptable salt thereof is administeredintravitreally on day 1, day 2, day 3 and day 4, and about 2.0 mg ofaflibercept is administered intravitreally on day 3. In one embodiment,about 0.3 mg or about 1.5 mg of Antagonist A or another pharmaceuticallyacceptable salt thereof is administered intravitreally on day 1, day 2,day 3 and day 4, and about 1.65 mg of pegaptanib sodium is administeredintravitreally on day 3.

In some embodiments, Antagonist A or another pharmaceutically acceptablesalt thereof and VEGF antagonist are administered every four weeks orevery 30 days, for six treatments. In some embodiments, the VEGFantagonist is ranibizumab. In some embodiments, 0.3 mg of Antagonist Aor another pharmaceutically acceptable salt thereof and 0.5 mg ofranibizumab are administered every four weeks or every 30 days, for sixtreatments. In some embodiments, 1.5 mg of Antagonist A or anotherpharmaceutically acceptable salt thereof and 0.5 mg of ranibizumab areadministered every four weeks or every 30 days, for six treatments.

In some embodiments, 0.3 mg of Antagonist A or another pharmaceuticallyacceptable salt thereof and 1.25 mg of bevacizumab, 2.0 mg ofaflibercept, or 1.65 mg of pegaptanib sodium are administered every fourweeks or every 30 days, for six treatments. In some embodiments, 1.5 mgof Antagonist A or another pharmaceutically acceptable salt thereof and1.25 mg of bevacizumab, 2.0 mg of aflibercept, or 1.65 mg of pegaptanibsodium are administered every four weeks or every 30 days, for sixtreatments.

In some embodiments, the methods comprise administering Antagonist A oranother pharmaceutically acceptable salt thereof, bevacizumab andaflibercept. In some embodiments, the methods comprise administeringAntagonist A or another pharmaceutically acceptable salt thereof,bevacizumab and aflibercept every four weeks or every 30 days, for sixtreatments. In some embodiments, the methods comprise administering 1.5mg of Antagonist A or another pharmaceutically acceptable salt thereof,1.25 mg of bevacizumab, and 2 mg of aflibercept. In some embodiments,the methods comprise administering 1.5 mg of Antagonist A or anotherpharmaceutically acceptable salt thereof, 1.25 mg of bevacizumab, and 2mg of aflibercept every four weeks or every 30 days, for six treatments.

In some embodiments, the methods comprise administering to a subject inneed thereof (a) Antagonist A or another pharmaceutically acceptablesalt thereof and (b) an VEGF antagonist, wherein (a) and (b) areadministered in an amount that is effective for treating or preventingan ocular condition (e.g., wet AMD), and wherein the administeringoccurs once every month, ±about seven days, for 12 consecutive months.

In some embodiments, the methods comprise administering to a subject inneed thereof (a) Antagonist A or another pharmaceutically acceptablesalt thereof and (b) an VEGF antagonist, wherein: (a) and (b) areadministered in an amount that is effective for treating or preventingan ocular condition (e.g., wet AMD); and the administering occurs onceevery month, ±about seven days, for a first 12 consecutive months, andimmediately thereafter once every two months, ±about seven days, for asecond 12 consecutive months, commencing on the second month of thesecond 12 consecutive months.

In some embodiments, the methods comprise administering to a subject inneed thereof (a) Antagonist A or another pharmaceutically acceptablesalt thereof and (b) an VEGF antagonist, wherein: (a) and (b) areadministered in an amount that is effective for treating or preventingan ocular condition (e.g., wet AMD); and the administering occurs onceevery month, ±about seven days, for 24 consecutive months is alsoprovided herein.

In some embodiments, the methods comprise administering to a subject inneed thereof (a) Antagonist A or another pharmaceutically acceptablesalt thereof and (b) an VEGF antagonist, wherein: (a) and (b) areadministered in an amount that is effective for treating or preventingan ocular condition (e.g., wet AMD); and the administering occurs onceevery month, ±about seven days, for three consecutive months, andimmediately thereafter once every two months, ±about seven days, for 12consecutive months, commencing on the second month of the 12 consecutivemonths.

In some embodiments, the methods comprise continuous treatment,continuous and discontinuous treatments, and/or retreatments, e.g., forthe treatment or preventing of wet-type AMD or subfoveal neovascularAMD. In some embodiments, continuous treatment comprises administeringto Antagonist A or another pharmaceutically acceptable salt thereof andan anti-VEGF agent monthly (±7 days) for at least 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, or 12 consecutive months. In some embodiments, AntagonistA or a pharmaceutically acceptable salt thereof is administered withinabout 1 min, about 2 min, about 5 min, about 10 min, about 15 min, about20 min, about 25 min, about 30 min, about 40 min, about 50 min, about 60min, about 90 min, about 2 hours, about 4 hours, about 6 hours, about 8hours, about 12 hours of administration of the VEGF antagonist. In someembodiments, the VEGF antagonist is administered prior to administrationof Antagonist A or a pharmaceutically acceptable salt thereof. In otherembodiments, Antagonist A or a pharmaceutically acceptable salt thereofis administered prior to administration of the VEGF antagonist. In someembodiments, Antagonist A or a pharmaceutically acceptable salt thereofand a VEGF antagonist are administered as a co-formulation. In someembodiments, the amount of Antagonist A or a pharmaceutically acceptablesalt thereof administered is about 1.5 mg/eye and the amount of VEGFantagonist administered is about 0.5 mg/eye (e.g., ranibizumab), about1.25 mg/eye (e.g., bevacizumab), about 1.65 mg/eye (e.g., pegaptanibsodium), or about 2.0 mg/eye (e.g., aflibercept).

In some embodiments, the methods further comprise measuring thesubject's visual acuity. In some embodiments, the subject's visualacuity is measured once every month, ±about seven days. In someembodiments, visual acuity is stable when it is stable for threeconsecutive months. In some embodiments, visual acuity is stable when ateach of the last two of the three consecutive months, visual acuity iswithin 5 ETDRS letters (better or worse) of the subject's visual acuityat the first of the three consecutive months (i.e., the monthimmediately preceding the first of the two consecutive followingmonths).

In some embodiments, a subject is administered in accordance with thepresent methods until the subject's visual acuity is stable. In someembodiments, a subject is administered in accordance with the presentmethods until the subject's visual acuity is stable for threeconsecutive months. In some embodiments, a subject is administered inaccordance with the present methods until the subject's visual acuity ateach of the last two of the three consecutive months is ≤afive-ETDRS-letter difference from the subject's visual acuity of thefirst of the three consecutive months. In some embodiments, a subject isadministered in accordance with the present methods until the subjectexperiences no new or significant intraretinal or sub-retinalhemorrhage, or no increase of ≥50 μm in foveal intraretinal fluid. Insome embodiments, a subject is administered in accordance with thepresent methods until the subject's visual acuity measured at each ofthe last two of the three consecutive months is ≤a five-ETDRS-letterdifference from the subject's visual acuity of the first of the threeconsecutive months, and the subject experiences no new or significantintraretinal or sub-retinal hemorrhage, and no increase of ≥50 μm infoveal intraretinal fluid.

In some embodiments, discontinuous treatment is administered aftercontinuous treatment, in which discontinuous treatment is based on aphysician's discretion, and the subject has stabilized vision asdetermined by ≤a five-ETDRS-letter difference in the subject's visualacuity after continuous and discontinuous treatment.

In some embodiments, subjects with a loss of visual acuity of >5 ETDRSletters from the previous monthly assessment, new and significantintraretinal or sub-retinal hemorrhage, and/or an increase of ≥50 μm infoveal intraretinal fluid are retreated.

In some embodiments, the continuous method comprises administeringAntagonist A or another pharmaceutically acceptable salt thereof and aVEGF antagonist in an amount that is effective for treating orpreventing wet AMD, wherein the administering occurs once every month,±about seven days, for 12 consecutive months. In some embodiments, themethods further comprise measuring the subject's visual acuity at onemonth, ±about seven days, immediately following the 12 consecutivemonths, wherein the subject's visual acuity measured on the twelfth ofthe 12 consecutive months and the one month immediately following the 12consecutive months is ≤a five-ETDRS-letter difference in the subject'svisual acuity measured on the eleventh of the 12 consecutive months.

In some embodiments, the methods further comprise measuring thesubject's visual acuity once every month, ±about seven days, on each ofan additional 11 consecutive months. In some embodiments, the subject'svisual acuity measured on any two consecutive months of the additional11 consecutive months is ≤a five-ETDRS-letter difference in thesubject's visual acuity measured on a month immediately preceding thetwo consecutive months.

In some embodiments, the subject's visual acuity measured on the twelfthof the 12 consecutive months and the one month immediately following the12 consecutive months is not ≤a five-ETDRS-letter difference in thesubject's visual acuity measured on the eleventh of the 12 consecutivemonths and the subject is retreated. In some embodiments, retreatmentcomprises administering to the patient on the one month immediatelyfollowing the 12 consecutive months Antagonist A or anotherpharmaceutically acceptable salt thereof and a VEGF antagonist in anamount that is effective for treating or preventing wet AMD, measuringthe patient's visual acuity on a month, ±about seven days, immediatelyfollowing the one month immediately following the 12 consecutive months,and administering to the subject on each immediately following monthAntagonist A or another pharmaceutically acceptable salt thereof and aVEGF antagonist in an amount that is effective for treating orpreventing wet AMD, until the subject's visual acuity on any twoconsecutive following months is ≤a five-ETDRS-letter difference in thesubject's visual acuity measured on a month immediately preceding thefirst of the two consecutive following months. In some embodiments, thetotal number of months does not exceed 24.

In some embodiments, wherein the subject's visual acuity measured on theone month immediately following the 12 consecutive months is not ≤afive-ETDRS-letter difference in the subject's visual acuity measured onthe twelfth of the 12 consecutive months and is not solely attributableto newly diagnosed foveal atrophy or worsening ocular media opacity, themethod further comprises administering to the subject on the one monthimmediately following the 12 consecutive months Antagonist A or anotherpharmaceutically acceptable salt thereof and a VEGF antagonist in anamount that is effective for treating or preventing wet AMD; andadministering to the subject on each immediately following month (a) and(b) in an amount that is effective for treating or preventing wet AMD,until the subject's visual acuity measured on any two consecutivefollowing months is ≤a five-ETDRS-letter difference in the subject'svisual acuity measured on a month immediately preceding the first of thetwo consecutive following months. In some embodiments, the total numberof months does not exceed 24.

In some embodiments, wherein the subject presents intraretinal orsub-retinal hemorrhage or a ≥50 μm increase in foveal intraretinal fluidat one month, ±about seven days, immediately following the 12consecutive months, the method further comprises administering to thesubject on the one month immediately following the 12 consecutive monthsAntagonist A or another pharmaceutically acceptable salt thereof an aVEGF antagonist in an amount that is effective for treating orpreventing wet AMD; and administering to the subject on each immediatelyfollowing month (a) and (b) in an amount that is effective for treatingor preventing wet AMD, until the subject's visual acuity measured on anytwo consecutive following months is ≤a five-ETDRS-letter difference inthe subject's visual acuity measured on a month immediately precedingthe first of the two consecutive following months. In some embodiments,the total number of months does not exceed 24.

Also provided herein is a method comprising administering Antagonist Aor another pharmaceutically acceptable salt thereof and a VEGFantagonist intravitreally once every month, ±about seven days, for afirst 12 consecutive months, and immediately thereafter once every twomonths, ±about seven days, for a second 12 consecutive months,commencing on the second month of the second 12 consecutive months. Insome embodiments, Antagonist A or a pharmaceutically acceptable saltthereof is administered within about 1 min, about 2 min, about 5 min,about 10 min, about 15 min, about 20 min, about 25 min, about 30 min,about 40 min, about 50 min, about 60 min, about 90 min, about 2 hours,about 4 hours, about 6 hours, about 8 hours, about 12 hours ofadministration of the VEGF antagonist. In some embodiments, the VEGFantagonist is administered prior to administration of Antagonist A or apharmaceutically acceptable salt thereof. In other embodiments,Antagonist A or a pharmaceutically acceptable salt thereof isadministered prior to administration of the VEGF antagonist. In someembodiments, Antagonist A or a pharmaceutically acceptable salt thereofand a VEGF antagonist are administered as a co-formulation. In someembodiments, the amount of Antagonist A or a pharmaceutically acceptablesalt thereof administered is about 1.5 mg/eye and the amount of VEGFantagonist administered is about 0.5 mg/eye (e.g., ranibizumab), about1.25 mg/eye (e.g., bevacizumab), about 1.65 mg/eye (e.g., pegaptanibsodium), or about 2.0 mg/eye (e.g., aflibercept).

In some embodiments, the method further comprises measuring thesubject's visual acuity once every month, ±about seven days, during thefirst 12 consecutive months and second 12 consecutive months. In someembodiments, the subject's visual acuity measured on any one of thefirst, third, fifth, seven, ninth and eleventh months of the secondconsecutive 12 months decreased at least five ETDRS letters relative tothe patient's visual acuity measured on the month immediately precedingthe first, third, fifth, seven, ninth or eleventh month of the secondconsecutive 12 months.

In some embodiments, the methods further comprises administering to thesubject an amount of Antagonist A or a pharmaceutically acceptable saltthereof and a VEGF antagonist effective for treating or preventing wetAMD on the month in which the subject's visual acuity measured thedecrease of at least five ETDRS letters relative to the patient's visualacuity measured on the immediately preceding month.

In some embodiments, the method further comprises administeringAntagonist A or a pharmaceutically acceptable salt thereof and a VEGFantagonist on any one of the first, third, fifth, seven, ninth andeleventh months of the second consecutive 12 months.

In some embodiments, the decrease in visual acuity is attributed tosolely newly diagnosed foveal atrophy or opacified ocular media.

In some embodiments, the subject presents intraretinal or sub-retinalhemorrhage or a ≥50 μm increase in foveal intraretinal fluid on any oneof the first, third, fifth, seven, ninth and eleventh months of thesecond consecutive 12 months.

In some embodiments, the method further comprises administeringAntagonist A or a pharmaceutically acceptable salt thereof and a VEGFantagonist on month in which the subject presents intraretinal orsub-retinal hemorrhage or a ≥50 μm increase in foveal intraretinalfluid.

Also provided herein is a method comprising administering Antagonist Aor another pharmaceutically acceptable salt thereof and a VEGFantagonist intravitreally once every month, ±about seven days, for 24consecutive months. In other embodiments, Antagonist A or anotherpharmaceutically acceptable salt thereof and a VEGF antagonist areadministered intravitreally once a month for three months and then everyother month for the next 21 months. In some embodiments, Antagonist A ora pharmaceutically acceptable salt thereof is administered within about1 min, about 2 min, about 5 min, about 10 min, about 15 min, about 20min, about 25 min, about 30 min, about 40 min, about 50 min, about 60min, about 90 min, about 2 hours, about 4 hours, about 6 hours, about 8hours, about 12 hours of administration of the VEGF antagonist. In someembodiments, the VEGF antagonist is administered prior to administrationof Antagonist A or a pharmaceutically acceptable salt thereof. In otherembodiments, Antagonist A or a pharmaceutically acceptable salt thereofis administered prior to administration of the VEGF antagonist. In someembodiments, Antagonist A or a pharmaceutically acceptable salt thereofand a VEGF antagonist are administered as a co-formulation. In someembodiments, the amount of Antagonist A or a pharmaceutically acceptablesalt thereof administered is about 1.5 mg/eye and the amount of VEGFantagonist administered is about 0.5 mg/eye (e.g., ranibizumab), about1.25 mg/eye (e.g., bevacizumab), about 1.65 mg/eye (e.g., pegaptanibsodium), or about 2.0 mg/eye (e.g., aflibercept).

In some embodiments, the methods comprise administering to a subject inneed thereof (a) Antagonist A or another pharmaceutically acceptablesalt thereof and (b) an VEGF antagonist, wherein (a) and (b) areadministered in an amount that is effective for treating or preventingan ophthalmological disease or disorder (e.g., wet AMD), and wherein theadministering occurs once every month, ±about seven days, for a firstadministration period of at least 3 consecutive months, followed byadministering (a) and (b) for a second administration period at afrequency of at least every other month ±about seven days beginning attwo months ±about seven days after the day of the last month of thefirst administration period on which (a) and (b) are administered. Insome embodiments, the first administration period is for at least 6consecutive months. In some embodiments, the VEGF antagonist isranibizumab or bevacizumab, wherein (a) and (b) are administered at afrequency of once every month ±about seven days during the secondadministration period and wherein the second administration period is atleast about nine months.

In some embodiments, the methods further comprise measuring thesubject's visual acuity on a day that is prior to and within about onemonth of administration of (a) and (b). In some embodiments, the methodsfurther comprise administering to the subject (a) and (b) in an amountthat is effective for treating or preventing an an ophthalmologicaldisease or disorder (e.g., wet AMD), until the subject's visual acuityon any two consecutive following months is ≤a five-ETDRS-letterdifference in the subject's visual acuity measured on a monthimmediately preceding the first of the two consecutive following months.

In some embodiments, the method further comprise administering to thesubject (a) and (b) every other month in an amount that is effective fortreating or preventing an an ophthalmological disease or disorder (e.g.,wet AMD), until the subject's visual acuity on any two consecutivevisual acuity assessments is not ≤a five-ETDRS-letter difference in thesubject's visual acuity measured on a visual acuity assessmentimmediately preceding the first of the two consecutive visual acuityassessments.

In other embodiments, the methods further comprise administering to thesubject (a) and (b) every month in an amount that is effective fortreating or preventing an an ophthalmological disease or disorder (e.g.,wet AMD), until the subject's visual acuity on any two consecutivefollowing months is ≤a five-ETDRS-letter difference in the subject'svisual acuity measured on a month immediately preceding the first of thetwo consecutive following months.

In some embodiments, the methods comprise administering to a subject inneed thereof (a) Antagonist A or another pharmaceutically acceptablesalt thereof and (b) aflibercept, wherein (a) and (b) are administeredin an amount that is effective for treating or preventing anophthalmological disease or disorder (e.g., wet AMD), and wherein theadministering occurs once every month, ±about seven days, for a firstadministration period of at least 3 consecutive months, followed byadministering (a) and (b) for a second administration period at afrequency of at least every other month ±about seven days beginning attwo months ±about seven days after the day of the last month of thefirst administration period on which (a) and (b) are administered.

In some embodiments, the subject has intraretinal or sub-retinalhemorrhage or a ≥50 μm increase in foveal intraretinal fluid at onemonth, ±about seven days, immediately following the secondadministration period. In some embodiments, the methods further compriseadministering to the subject on each month ±about seven days, beginningon the month that immediately follows the second administration period(a) and (b) in an amount that is effective for treating or preventingwet AMD, until the subject's visual acuity measured on any twoconsecutive months that follow the 12 consecutive months is ≤afive-ETDRS-letter difference in the subject's visual acuity measured ona month immediately preceding the first of the two consecutive months.

In some embodiments, the total number of months of treatment does notexceed 24.

Pharmaceutical compositions according to the invention may be formulatedto release Antagonist A or another pharmaceutically acceptable saltthereof, a VEGF antagonist, or an anti-C5 agent, substantiallyimmediately upon administration or at any predetermined time periodafter administration, using controlled release formulations. Forexample, a pharmaceutical composition can be provided insustained-release form. The use of immediate or sustained releasecompositions depends on the nature of the condition being treated. Ifthe condition consists of an acute disorder, treatment with an immediaterelease form can be utilized over a prolonged release composition. Forcertain preventative or long-term treatments, a sustained releasedcomposition can also be appropriate.

Administration of one or both of the antagonists of, or an anti-C5agent, in controlled release formulations can be useful where theantagonist, either alone or in combination, has (i) a narrow therapeuticindex (e.g., the difference between the plasma concentration leading toharmful side effects or toxic reactions and the plasma concentrationleading to a therapeutic effect is small; generally, the therapeuticindex, TI, is defined as the ratio of median lethal dose (LD₅₀) tomedian effective dose (ED₅₀)); (ii) a narrow absorption window in thegastro-intestinal tract; or (iii) a short biological half-life, so thatfrequent dosing during a day is required in order to sustain the plasmalevel at a therapeutic level.

Many strategies can be pursued to obtain controlled release in which therate of release outweighs the rate of degradation or metabolism of thetherapeutic antagonist. For example, controlled release can be obtainedby the appropriate selection of formulation parameters and ingredients,including, e.g., appropriate controlled release compositions andcoatings. Examples include single or multiple unit tablet or capsulecompositions, oil solutions, suspensions, emulsions, microcapsules,microspheres, nanoparticles, patches, and liposomes. Methods forpreparing such sustained or controlled release formulations are wellknown in the art.

Antagonist A or another pharmaceutically acceptable salt thereof, theVEGF antagonist, or the anti-C5 agent can also be delivered using adrug-delivery device such as an implant. Such implants can bebiodegradable and/or biocompatible, or can be non-biodegradable. Theimplants can be permeable to Antagonist A or another pharmaceuticallyacceptable salt thereof, the VEGF antagonist, or the anti-C5 agent.Ophthalmic drug delivery devices can be inserted into a chamber of theeye, such as the anterior or posterior chamber or can be implanted in oron the sclera, choroidal space, or an avascularized region exterior tothe vitreous. In one embodiment, the implant can be positioned over anavascular region, such as on the sclera, so as to allow for transcleraldiffusion of Antagonist A or another pharmaceutically acceptable saltthereof, the VEGF antagonist, or the anti-C5 agent to the desired siteof treatment, e.g., the intraocular space and macula of the eye.Furthermore, the site of transcleral diffusion can be proximal to a siteof neovascularization such as a site proximal to the macula. Suitabledrug delivery devices are described, for example, in U.S. PublicationNos. 2008/0286334; 2008/0145406; 2007/0184089; 2006/0233860;2005/0244500; 2005/0244471; and 2005/0244462, and U.S. Pat. Nos.6,808,719 and 5,322,691, the contents of each of which is hereinincorporated by reference in its entirety.

In one embodiment, the implant comprises Antagonist A or anotherpharmaceutically acceptable salt thereof and/or VEGF antagonistdispersed in a biodegradable polymer matrix. The matrix can comprisePLGA (polylactic acid-polyglycolic acid copolymer), an ester-end cappedpolymer, an acid end-capped polymer, or a mixture thereof. In anotherembodiment, the implant comprises Antagonist A or anotherpharmaceutically acceptable salt thereof and/or a VEGF antagonist, asurfactant, and lipophilic compound. The lipophilic compound can bepresent in an amount of about 80-99% by weight of the implant. Suitablelipophilic compounds include, but are not limited to, glycerylpalmitostearate, diethylene glycol monostearate, propylene glycolmonostearate, glyceryl monostearate, glyceryl monolinoleate, glycerylmonooleate, glyceryl monopalmitate, glyceryl monolaurate, glyceryldilaurate, glyceryl monomyristate, glyceryl dimyristate, glycerylmonopalmitate, glyceryl dipalmitate, glyceryl monostearate, glyceryldistearate, glyceryl monooleate, glyceryl dioleate, glycerylmonolinoleate, glyceryl dilinoleate, glyceryl monoarachidate, glyceryldiarachidate, glyceryl monobehenate, glyceryl dibehenate, and mixturesthereof. In another embodiment, the implant comprises Antagonist A oranother pharmaceutically acceptable salt thereof and/or a VEGFantagonist housed within a hollow sleeve. The PDGF antagonist or VEGFantagonist, or both, are delivered to the eye by inserting the sleeveinto the eye, releasing the implant from the sleeve into the eye, andthen removing the sleeve from the eye. An example of this deliverydevice is described in U.S. Publication No. 2005/0244462, which ishereby incorporated by reference in its entirety.

In one embodiment, the implant is a flexible ocular insert deviceadapted for the controlled sustained release of Antagonist A or anotherpharmaceutically acceptable salt thereof and/or a VEGF antagonist intothe eye. In one embodiment, the device includes an elongated body of apolymeric material in the form of a rod or tube containing Antagonist Aor another pharmaceutically acceptable salt thereof, VEGF antagonist orboth, and with at least two anchoring protrusions extending radiallyoutwardly from the body. The device may have a length of at least 8 mmand the diameter of its body portion including the protrusions does notexceed 1.9 mm. The sustained release mechanism can, for example, be bydiffusion or by osmosis or bioerosion. The insert device can be insertedinto the upper or lower formix of the eye so as to be independent ofmovement of the eye by virtue of the formix anatomy. The protrusions canbe of various shapes such as, for example, ribs, screw threads, dimplesor bumps, truncated cone-shaped segments or winding braid segments. In afurther embodiment, the polymeric material for the body is selected asone which swells in a liquid environment. Thus a device of smallerinitial size can be employed. The insert device can be of a size andconfiguration such that, upon insertion into the upper or lower formix,the device remains out of the field of vision so as to be well retainedin place and imperceptible by a recipient over a prolonged period ofuse. The device can be retained in the upper or lower formix for 7 to 14days or longer. An example of this device is described in U.S. Pat. No.5,322,691, which is hereby incorporated by reference in its entirety.

Kits

The invention relates to kits comprising one or more pharmaceuticalcompositions and instructions for use. At least two antagonists can beformulated together or in separate compositions and in individual dosageamounts. The antagonists are also useful when formulated aspharmaceutically acceptable salts. In one embodiment, the kits comprisea composition comprising Antagonist A or another pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier orvehicle and another composition comprising a VEGF antagonist and apharmaceutically acceptable carrier or vehicle. In another embodiment,the kits comprise a composition comprising a VEGF antagonist, AntagonistA or another pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier or vehicle. Each of the kits'compositions can be contained in a container. In some embodiments, thekits comprise an anti-C5 agent.

The kits can comprise (1) an amount of Antagonist A or anotherpharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier, vehicle, or diluent in a first unit dosage form; (2)an amount of a VEGF antagonist and a pharmaceutically acceptablecarrier, vehicle, or diluent in a second unit dosage form; and (3) acontainer. The container can be used to separate components and include,for example, a divided bottle or a divided foil packet. The separateantagonist compositions may also, if desired, be contained within asingle, undivided container. In some embodiments, the kits comprise ananti-C5 agent.

The kits can also comprise directions for the administration of theantagonists. The kits are particularly advantageous when the separatecomponents are administered in different dosage forms, are administeredat different dosage levels, or when titration of the individualantagonists is desired.

EXAMPLES Example 1: Antagonist A and Ranibizumab Combination Therapy forTreating Subfoveal Neovascular Lesions Secondary to NeovascularAge-Related Macular Degeneration (NVAMD)

In this study, 449 subjects with subfoveal neovascular lesions secondaryto NVAMD received six monthly intravitreous injections of Antagonist Agiven in combination with ranibizumab (administered as Lucentis®,commercially available from Genentech, South San Francisco, Calif.).Antagonist A was injected as the formulation shown in Table 12. Theprimary efficacy endpoint in the study was the mean change in visualacuity from baseline at the week 24 visit. As pre-specified in theanalysis plan, the Hochberg procedure (Hochberg, Y. (1988). A sharperBonferroni procedure for multiple tests of significance. Biometrika. 75,800-802) was employed to account for multiple dose comparisons.

The subjects were randomized in a 1:1:1 ratio to the groups shown inTable 13.

TABLE 12 Antagonist A Formulation 30 mg/mL Reference to Solution PercentName of Ingredient Standards Function Composition (w/v) Antagonist AIn-house standard Drug substance 30.0 mg   3% Monobasic Sodium USP/Ph.Eur pH buffering agent 0.3 mg 0.03% Phosphate Monohydrate Dibasic SodiumPhos- USP/Ph. Eur pH buffering agent 2.1 mg  0.2% phate HeptahydrateSodium Chloride USP/Ph. Eur Tonicity adjuster 9.0 mg  0.9% HydrochloricAcid NF/Ph. Eur pH adjuster As needed Sodium Hydroxide NF/Ph. Eur pHadjuster As needed Water for Injection USP/Ph. Eur Diluent q.s. 95.9%Nitrogen NF/Ph. Eur Inert gas overlay — — Total Volume 1 ml Volume inFinal Drug 230 microliters Product Presentation

TABLE 13 Antagonist A and Ranibizumab Combination Therapy for SubfovealNeovascular Lesions Secondary to NVAMD Treatment Groups Group No . GroupName Treatment Regimen 1 Combination Subjects were administered 0.3mg/eye of Therapy (0.3 mg) Antagonist A and 0.5 mg/eye of Lucentis ® 2Combination Subjects were administered 1.5 mg/eye of Therapy (1.5 mg)Antagonist A and 0.5 mg/eye of Lucentis ® 3 Ranibizumab Subjects wereadministered Antagonist A Monotherapy Sham and 0.5 mg/eye of Lucentis ®

Combination therapy proved superior in terms of mean visual gain whencompared to eyes that were treated with anti-VEGF monotherapy. Subjectstreated with Lucentis® and either 1.5 mg/eye or 0.3 mg/eye Antagonist Ashowed an increase in visual acuity compared with those treated withLucentis® alone (FIG. 2). The combination of 1.5 mg/eye of Antagonist Aand 0.5 mg of Lucentis® met the pre-specified, alpha protected primaryendpoint of superiority in mean change of visual acuity gain compared toranibizumab monotherapy from baseline to 24 weeks (10.6 ETDRS letters atweek 24, compared to 6.5 letters, p=0.019, representing a 62% additionalbenefit). (FIG. 3) Subjects treated with Lucentis® and either 1.5 mg or0.3 mg Antagonist A showed a 62% comparative benefit from baselinecompared to treatment with Lucentis® alone.

In addition, the mean change in vision over time demonstrated thebenefit of combination therapy at each measured time point over 24weeks. (FIG. 4) That benefit was sustained during the study anddemonstrated increasing differentiation of the curves at study closure.

Treatment with 0.5 mg of Lucentis® and either 1.5 mg or 0.3 mgAntagonist A in wet AMD patients also had increased efficacy as comparedto patients treated with Lucentis® alone, independent of baseline lesionsize or vision. (FIGS. 5A and 5B)

A greater percentage of subjects in the Combination Therapy (1.5 mg)group achieved enhanced visual outcomes compared to those in theRanibizumab Monotherapy group with respect to multiple treatmentendpoints at week 24, as shown in FIG. 6A, and Table 14.

TABLE 14 Percentage of Subjects in the Combination Therapy (1.5 mg)Group and Ranibizumab Monotherapy Group with Visual Acuity ImprovementPercentage of Patients Combination Therapy Ranibizumab TreatmentEndpoint (1.5 mg) Monotherapy >3-lines of visual acuity 36.4% 28.6%improvement >4-lines of visual acuity 19.9% 11.6% improvement >5-linesof visual acuity 11.9% 4.1% improvement ≥20/40 vision 37.0% 31.9% aftertreatment ≥20/25 vision 12.3% 5.6% after treatment

Moreover, fewer subjects in the Combination Therapy (1.5 mg) groupdemonstrated a loss of visual acuity as compared to the number ofsubjects in the Ranibizumab Monotherapy group at week 24, as shown inFIG. 6B and Table 15.

TABLE 15 Percentage of Subjects in the Combination Therapy (1.5 mg)Group and Ranibizumab Monotherapy Group with Visual Acuity LossPercentage of Patients Combination Therapy Ranibizumab TreatmentEndpoint (1.5 mg) Monotherapy ≥1-lines of 8.3% 21.5% visual acuity loss≥2-lines of 3.4% 12.5% visual acuity loss ≤20/125 vision 19.2% 27.8%after treatment ≤20/200 vision 10.3% 13.9% after treatment

Subjects treated with Lucentis® and 1.5 mg Antagonist A showed improvedfinal visual acuity compared to patients treated with Lucentis®monotherapy. (FIG. 7) Subjects in the Combination Therapy (1.5 mg) groupalso showed increased reduction in CNV size in small and large baselineCNV as compared to subjects in the Ranibizumab Monotherapy group (FIGS.8A and 8B).

Combination therapy was well tolerated. There were no events ofendophthalmitis, retinal detachment, retinal tear or iatrogenictraumatic cataract after a total of 4431 intravitreal injections (1776administrations of Antagonist A and 2655 administrations of Lucentis®).As expected, mean intraocular pressure (IOP) increased after eachintravitreal injection consistent with a volume effect. However, meanIOP in all arms returned to pre-injection levels at the next visit,including at the end of the study. The systemic safety profile ofcombination therapy was similar to that of ranibizumab monotherapy.

The results of the trial show statistically significant superiorefficacy of the combination treatment with Antagonist A and ranibizumabover Lucentis® (ranibizumab) monotherapy for the treatment of wet AMD.

Example 2: ARC1905 for the Treatment of Wet AMD

Forty-three patients with subfoveal neovascular AMD received six monthlyadministrations of ARC1905 (0.3 mg/eye, 1 mg/eye or 2 mg/eye) incombination with Lucentis. The mean change in visual acuity at week 24was an increase of +13.6, +11.7 and +15.3 letters at the doses of 0.3mg, 1 mg and 2 mg, respectively. Furthermore, 46%, 47% and 60% ofpatients gained 3 or more lines of visual acuity at the doses of 0.3 mg,1 mg, and 2 mg, respectively.

Example 3: ARC1905 for the Treatment and Prevention of Dry AMD

Forty-seven patients with dry AMD were enrolled to receive fiveintravitreal injections of either 0.3 mg/eye or 1.0 mg/eye of ARC1905over a 36-week treatment period. FIG. 9 shows the mean change ingeographic atrophy (GA) lesion area in dry AMD patients measured at week24 in patients treated with either 0.3 mg or 1.0 mg doses of ARC1905 atweeks 0, 4, and 8. FIG. 10 shows the mean change in GA lesion in dry AMDpatients measured at week 24 and week 48 in patients treated with either0.3 mg or 1.0 mg doses of ARC1905 at weeks 0, 4, 8, 24, and 36. Theresults show a dose-dependent reduction in growth of the GA lesion,indicating ARC1905 can slow the progression of GA in non-exudative typeAMD patients

Example 4: Visual Acuity Testing Using ETDRS Chart

Best-corrected visual acuity is measured using standard charts,lighting, and procedures. Best correction is determined by carefulrefraction at that visit.

Chart 1 (FIG. 11) is used for testing the visual acuity of the righteye. Chart 2 (FIG. 12) is used for testing the left eye. Chart R (FIG.13) is used for testing refraction. Subjects do not see any of thecharts before the examination.

A distance of 4 meters is between the subject's eyes and the visualacuity chart. With the box light off, not more than 15 foot-candles oflight (161.4 Lux) fall on the center of the chart. To measure the amountof light, the room is set up for visual acuity testing, but with the boxlight off. The light meter is placed at the fourth line from the top ofthe chart, with its back against the chart and the reading is taken. Ifmore than one lane is available for testing visual acuity, the visualacuity of an individual subject should be measured in the same lane ateach visit. If different lanes are used to test visual acuity, they eachmeet the same standards.

Retroilluminated ETDRS charts are used. The illuminator box is eitherwall-mounted or mounted on a stand (available from Lighthouse Low VisionServices). The light box is mounted at a height such that the top of thethird row letter is 49±2 inches from the floor.

The visual acuity light box is equipped with two 20-watt fluorescenttubes (available from General Electric Cool Daylight) and a ballastwhich partially covers the tubes. Because the illumination offluorescent tubes generally diminishes by 5 percent during the first 100hours and by another 5 percent during the next 2000 hours, new tubes arekept on for 4 days (96 hours) continuously, and replaced once a year.

A sticker is placed on the back of the light box, indicating the date onwhich the present tubes were installed. A spare set of burned in bulbsis available.

Each tube is partly covered by a 14-inch fenestrated sleeve, which isopen in the back. This serves as a baffle to reduce illumination. Eachsleeve is centered on the tube with the opening towards the back.

All eyes are tested at 4 meters first, even if the refraction wasperformed at 1 meter. The subject is seated comfortably directly infront of the chart so that the eyes remain at the 4 meter distance.Testing begins with the right eye. The subject's left eye is occluded. Afolded tissue or eye pad lightly taped over the eye behind the trialframe serves as an effective occluder that allows eccentric fixationwithout inadvertent use of the covered eye. After testing the right eye,occlusion of the right eye is done before Chart 2 is put up for testingthe left eye.

The lens correction from the subjective refraction is in the trial frameworn by the subject.

The subject is asked to read the letters slowly, approximately oneletter per second. The subject is told that only one chance is given toread each letter on the chart. If the subject is unsure about theidentity of the letter, then the subject is encouraged to guess.

The subject begins by reading the top line of the chart and continuereading every letter on each smaller line, from left to right on eachline. The examiner circles every correct letter read and totals eachline and the whole column (0 if no letters are correct) on the datacollection form. An X is put through letters read incorrectly. Letters,for which no guess was attempted, are not circled. When a subjectreaches a level where he/she cannot guess, the examiner may stop thetest provided that the subject has made errors on previous guesses,which is a clear indication that the best visual acuity has beenobtained.

When a subject cannot read at least 20 letters on the chart at 4.0meters, the subject is tested at 1.0 meter. The distance from thesubject to the chart should be measured again using the rigid one meterstick. The distance is measured from the outer canthus to the center ofthe fourth letter (right eye) or the second letter (left eye) of thethird line of the chart. The spherical correction in the trial frameshould be changed by adding +0.75 to correct for the closer testdistance. The subject may fixate eccentrically or turn or shake his/herhead to improve visual acuity. If this is done, the examiner ensuresthat the fellow eye remains occluded both centrally and peripherally andthat the subject does not move forward in the chair. Particular careshould be taken to ensure the subject does not move forward when testingat 1 meter. The subject is reminded to blink.

The examiner does not tell the subject if a letter was identifiedcorrectly. The subject may be encouraged by neutral comments, such as“good”, “next”, and “OK”.

The examiner does not stand close to the chart during testing. Theexaminer's attention is focused on the subject and the data collectionform. If the subject has difficulty locating the next line to read, theexaminer may go up to the chart and point to the next line to be read,and then moves away from the chart.

When it is possible to measure the visual acuity of the eye at 4.0meters (i.e., 20 or more letters read at 4 meters), the visual acuityscore for that eye is recorded as the number of letters correct plus 30.The subject gets credit for the 30 1M letters even though they did nothave to read them. Otherwise, the visual acuity score is the number ofletters read correctly at 1.0 meter plus the number, if any, read at 4M.If no letters are read correctly at either 4.0 meters or 1 meter, thenthe visual acuity score is recorded as 0.

INCORPORATION BY REFERENCE

All publications and patent applications disclosed in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

What is claimed is:
 1. A method of treating geographic atrophy in ahuman subject in need thereof, the method comprising administering viaintravitreal injection to said subject about 2 mg/eye of a pegylatedaptamer in an amount sufficient to reduce growth of a lesion associatedwith geographic atrophy in the subject, wherein the aptamer comprisesthe sequence fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUfUAfCfCfUmGfCmG-3T (SEQ ID NO:26), wherein fC and fU=2′fluoro nucleotides, mG and mA=2′-OMe nucleotides, all other nucleotidesare 2′-OH, and 3T indicates an inverted deoxythymidine, or a saltthereof, and wherein the pegylated aptamer is administered to thesubject biweekly, monthly, or quarterly.
 2. The method according toclaim 1, wherein the pegylated aptamer is provided as a pegylated moietyconjugated to the aptamer via a linker.
 3. The method according to claim2, wherein the pegylated moiety is conjugated to the 5′ end of theaptamer.
 4. The method according to claim 2, wherein the pegylatedmoiety is a branched PEG.
 5. The method according to claim 2, whereinthe pegylated moiety has a molecular weight greater than about 10 kDA.6. The method according to claim 2, wherein the pegylated moiety has amolecular weight of about 40 kDa.
 7. The method according to claim 1,wherein the pegylated moiety has the following structure:


8. The method according to claim 1, wherein the growth of the GA lesionin the subject in need thereof is reduced by at least 10%, as comparedto a subject who is not administered the anti-C5 agent.
 9. The methodaccording to claim 1, wherein the anti-C5 agent is administered monthly.10. The method according to claim 9, wherein the anti-C5 agent isadministered monthly for three injections, and the fourth and fifthinjections are administered three or four months after the thirdinjection.
 11. The method according to claim 1, wherein the anti-C5agent is administered bimonthly.
 12. The method according to claim 1,wherein the anti-C5 agent is administered quarterly.
 13. The methodaccording to claim 1, wherein the growth of the GA lesion in the subjectin need thereof is reduced by at least 20% as compared to a subject whois not administered the anti-C5 agent.
 14. The method according to claim1, wherein the growth of the GA lesion in the subject in need thereof isreduced by at least 30% as compared to a subject who is not administeredthe anti-C5 agent.
 15. The method according to claim 1, wherein thegrowth of the GA lesion in the subject in need thereof is reduced by atleast 40% as compared to a subject who is not administered the anti-C5agent.
 16. The method according to claim 1, wherein the growth of the GAlesion in the subject in need thereof is reduced by at least 50% ascompared to a subject who is not administered the anti-C5 agent.
 17. Themethod according to claim 1, wherein growth of the lesion is assessedusing autofluorescence imaging or optical coherence tomography.
 18. Amethod of treating geographic atrophy in a human subject in needthereof, the method comprising administering via intravitreal injectionto said subject about 2 mg/eye of a pegylated aptamer in an amountsufficient to reduce growth of a lesion associated with geographicatrophy in the subject, wherein the aptamer comprises the sequencefCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUfUAfCfCfUmGfCmG-3T (SEQ ID NO:26), wherein fC and fU=2′fluoro nucleotides, mG and mA=2′-OMe nucleotides, all other nucleotidesare 2′-OH, and 3T indicates an inverted deoxythymidine, or a saltthereof, and wherein the pegylated aptamer is administered to thesubject biweekly, monthly, or quarterly, wherein the pegylated moiety isa branched PEG and has a molecular weight greater than about 10 kDA, andwherein the growth of the GA lesion in the subject in need thereof isreduced by at least 30% as compared to a subject who is not administeredthe anti-C5 agent.
 19. A method of treating geographic atrophy in ahuman subject in need thereof, the method comprising administering viaintravitreal injection to said subject about 2 mg/eye of a pegylatedaptamer in an amount sufficient to reduce growth of a lesion associatedwith geographic atrophy in the subject, wherein the aptamer comprisesthe sequence fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUfUAfCfCfUmGfCmG-3T (SEQ ID NO:26), wherein fC and fU=2′fluoro nucleotides, mG and mA=2′-OMe nucleotides, all other nucleotidesare 2′-OH, and 3T indicates an inverted deoxythymidine, or a saltthereof, and wherein the pegylated aptamer is administered to thesubject biweekly, monthly, or quarterly, wherein the pegylated moiety isa branched PEG and has a molecular weight greater than about 10 kDA, andwherein the growth of the GA lesion in the subject in need thereof isreduced by at least 40% as compared to a subject who is not administeredthe anti-C5 agent.